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url: http://arxiv.org/abs/q-bio/0401039v1
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[q-bio/0401039v1] Regulation of Neuromodulator Receptor Efficacy - Implications for Whole-Neuron and Synaptic Plasticity

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# Quantitative Biology > Molecular Networks

**arXiv:q-bio/0401039v1** (q-bio) 

[Submitted on 28 Jan 2004]

# Title:Regulation of Neuromodulator Receptor Efficacy - Implications for Whole-Neuron and Synaptic Plasticity

Authors:[Gabriele Scheler](https://arxiv.org/search/q-bio?searchtype=author&query=Scheler,+G)

View a PDF of the paper titled Regulation of Neuromodulator Receptor Efficacy - Implications for Whole-Neuron and Synaptic Plasticity, by Gabriele Scheler

[View PDF](/pdf/q-bio/0401039v1)

> Abstract: Membrane receptors for neuromodulators (NM) are highly regulated in their distribution and efficacy - a phenomenon which influences the individual cell's response to central signals of NM release. Even though NM receptor regulation is implicated in the pharmacological action of many drugs, and is also known to be influenced by various environmental factors, its functional consequences and modes of action are not well understood. In this paper we summarize relevant experimental evidence on NM receptor regulation (specifically dopamine D1 and D2 receptors) in order to explore its significance for neural and synaptic plasticity. We identify the relevant components of NM receptor regulation (receptor phosphorylation, receptor trafficking and sensitization of second-messenger pathways) gained from studies on cultured cells. Key principles in the regulation and control of short-term plasticity (sensitization) are identified, and a model is presented which employs direct and indirect feedback regulation of receptor efficacy. We also discuss long-term plasticity which involves shifts in receptor sensitivity and loss of responsivity to NM signals. Finally, we discuss the implications of NM receptor regulation for models of brain plasticity and memorization. We emphasize that a realistic model of brain plasticity will have to go beyond Hebbian models of long-term potentiation and depression. Plasticity in the distribution and efficacy of NM receptors may provide another important source of functional plasticity with implications for learning and memory. 

Comments: | 35 pages  
---|---  
Subjects: |  Molecular Networks (q-bio.MN); Neurons and Cognition (q-bio.NC)  
Cite as: | [arXiv:q-bio/0401039](https://arxiv.org/abs/q-bio/0401039) [q-bio.MN]  
  | (or  [arXiv:q-bio/0401039v1](https://arxiv.org/abs/q-bio/0401039v1) [q-bio.MN] for this version)   
  |  <https://doi.org/10.48550/arXiv.q-bio/0401039> Focus to learn more arXiv-issued DOI via DataCite  
Journal reference: | Progress in Neurobiology 72(6), pp 399-415, April 2004  
Related DOI:  | <https://doi.org/10.1016/j.pneurobio.2004.03.008> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Gabriele Scheler [[view email](/show-email/4117a7f9/q-bio/0401039)]   
**[v1]** Wed, 28 Jan 2004 04:28:04 UTC (76 KB)  


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url: http://arxiv.org/abs/2308.11936v2
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[2308.11936v2] General Chemical Reaction Network Theory for Olfactory Sensing Based on G-Protein-Coupled Receptors : Elucidation of Odorant Mixture Effects and Agonist-Synergist Threshold

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# Quantitative Biology > Molecular Networks

**arXiv:2308.11936v2** (q-bio) 

[Submitted on 23 Aug 2023 ([v1](https://arxiv.org/abs/2308.11936v1)), last revised 5 Sep 2023 (this version, v2)]

# Title:General Chemical Reaction Network Theory for Olfactory Sensing Based on G-Protein-Coupled Receptors : Elucidation of Odorant Mixture Effects and Agonist-Synergist Threshold

Authors:[Won Kyu Kim](https://arxiv.org/search/q-bio?searchtype=author&query=Kim,+W+K), [Kiri Choi](https://arxiv.org/search/q-bio?searchtype=author&query=Choi,+K), [Changbong Hyeon](https://arxiv.org/search/q-bio?searchtype=author&query=Hyeon,+C), [Seogjoo J. Jang](https://arxiv.org/search/q-bio?searchtype=author&query=Jang,+S+J)

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> Abstract:This work presents a general chemical reaction network theory for olfactory sensing processes that employ G-protein-coupled receptors as olfactory receptors (ORs). The theory is applicable to general mixtures of odorants and an arbitrary number of ORs. Reactions of ORs with G-proteins, both in the presence and the absence of odorants, are explicitly considered. A unique feature of the theory is the definition of an odor activity vector consisting of strengths of odorant-induced signals from ORs relative to those due to background G-protein activity in the absence of odorants. It is demonstrated that each component of the odor activity defined this way reduces to a Michaelis-Menten form capable of accounting for cooperation or competition effects between different odorants. The main features of the theory are illustrated for a two-odorant mixture. Known and potential mixture effects, such as suppression, shadowing, inhibition, and synergy are quantitatively described. Effects of relative values of rate constants, basal activity, and G-protein concentration are also demonstrated. 

Subjects: |  Molecular Networks (q-bio.MN); Biological Physics (physics.bio-ph); Chemical Physics (physics.chem-ph)  
---|---  
Cite as: | [arXiv:2308.11936](https://arxiv.org/abs/2308.11936) [q-bio.MN]  
  | (or  [arXiv:2308.11936v2](https://arxiv.org/abs/2308.11936v2) [q-bio.MN] for this version)   
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## Submission history

From: Won Kyu Kim [[view email](/show-email/edd815e6/2308.11936)]   
**[[v1]](/abs/2308.11936v1)** Wed, 23 Aug 2023 05:59:45 UTC (3,370 KB)  
**[v2]** Tue, 5 Sep 2023 03:44:58 UTC (3,370 KB)  


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url: http://arxiv.org/abs/1407.4750v1
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[1407.4750v1] Ligand-dependent opening of the multiple AMPA receptor conductance states: a concerted model

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# Quantitative Biology > Molecular Networks

**arXiv:1407.4750v1** (q-bio) 

[Submitted on 17 Jul 2014]

# Title:Ligand-dependent opening of the multiple AMPA receptor conductance states: a concerted model

Authors:[Ranjita Dutta Roy](https://arxiv.org/search/q-bio?searchtype=author&query=Roy,+R+D), [Christian Rosenmund](https://arxiv.org/search/q-bio?searchtype=author&query=Rosenmund,+C), [Stuart J Edelstein](https://arxiv.org/search/q-bio?searchtype=author&query=Edelstein,+S+J), [Nicolas Le Novère](https://arxiv.org/search/q-bio?searchtype=author&query=Nov%C3%A8re,+N+L)

View a PDF of the paper titled Ligand-dependent opening of the multiple AMPA receptor conductance states: a concerted model, by Ranjita Dutta Roy and Christian Rosenmund and Stuart J Edelstein and Nicolas Le Nov\\`ere

[View PDF](/pdf/1407.4750v1)

> Abstract:Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms behind synaptic plasticity in the central nervous system of vertebrates. Electrophysiological recordings of single channels stimulated with agonists showed that both recombinant and native AMPA receptors visit multiple conductance states in an agonist concentration dependent manner. We propose an allosteric model of the multiple conductance states based on concerted conformational transitions of the four subunits, as an iris diaphragm. Our model predicts that the thermodynamic behaviour of the conductance states upon full and partial agonist stimulations can be described with increased affinity of receptors as they progress to higher conductance states. The model also predicts existence of AMPA receptors in non-liganded conductive substates. However, spontaneous openings probability decreases with increasing conductances. Finally, we predict that the large conductance states are stabilized within the rise phase of a whole-cell EPSC in glutamatergic hippocampal neurons. Our model provides a mechanistic link between ligand concentration and conductance states that can explain thermodynamic and kinetic features of AMPA receptor gating. 

Comments: | 4 figures, models available on demand. They will be published by BioModels Database upon publication of the article  
---|---  
Subjects: |  Molecular Networks (q-bio.MN); Subcellular Processes (q-bio.SC)  
Cite as: | [arXiv:1407.4750](https://arxiv.org/abs/1407.4750) [q-bio.MN]  
  | (or  [arXiv:1407.4750v1](https://arxiv.org/abs/1407.4750v1) [q-bio.MN] for this version)   
  |  <https://doi.org/10.48550/arXiv.1407.4750> Focus to learn more arXiv-issued DOI via DataCite  
Related DOI:  | <https://doi.org/10.1371/journal.pone.0116616> Focus to learn more DOI(s) linking to related resources   
  
## Submission history

From: Nicolas Le Novère [[view email](/show-email/db021dc7/1407.4750)]   
**[v1]** Thu, 17 Jul 2014 17:42:45 UTC (689 KB)  


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#  Creatine Supplementation for Health and Clinical Diseases 

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A special issue of [_Nutrients_](/journal/nutrients) (ISSN 2072-6643). This special issue belongs to the section "[Sports Nutrition](/journal/nutrients/sections/Sport_Nutrition)".

Deadline for manuscript submissions: **closed (31 December 2021)** | Viewed by 698277    


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**Interests:** exercise physiology; sports nutrition; performance enhancement; weight loss; women's health  
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Special Issue in [ _Sports_ : Cutting-Edge Strategies in Resistance Training: Exploring Innovative Approaches](/journal/sports/special_issues/VHAKT77C3E)  


![](/data/editors/editor_93877.png?1647247286) Prof. Dr. Jeffrey R. Stout 

![](/data/editors/editor_93877.png?1647247286) Prof. Dr. Jeffrey R. Stout 

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_Guest Editor_  


Physiology of Work and Exercise Response (POWER) Laboratory, Institute of Exercise Physiology and Rehabilitation Science, School of Kinesiology and Physical Therapy University of Central Florida, 12494 University Blvd., Orlando, FL 32816, USA  
**Interests:** resistance training; nutrition; ergogenic aids; dietary supplements; body composition; muscle fatigue  
Special Issues, Collections and Topics in MDPI journals

Special Issue in [ _Nutrients_ : Creatine Supplementation in Health, Performance, Disease and Rehabilitation](/journal/nutrients/special_issues/creatine_health)  
Special Issue in [ _Sports_ : Cutting-Edge Strategies in Resistance Training: Exploring Innovative Approaches](/journal/sports/special_issues/VHAKT77C3E)  


## Special Issue Information

Dear Colleagues,

Creatine supplementation is one of the most studied and effective ergogenic aids for athletes. The multifaceted mechanisms by which creatine exerts its beneficial effect include increasing anaerobic energy capacity, increasing protein synthesis, and decreasing protein breakdown, leading to increased muscle mass and physical performance. While these well-recognized creatine effects benefit the athlete, creatine may also serve as a potential clinical and therapeutic supplementary treatment to conventional medical interventions. Several studies have examined the effects on conditions such as diabetes, sarcopenia, osteoporosis, cancer, rehabilitation, and pulmonary and cardiovascular health. This Special Issue aims to provide comprehensive reviews of creatine supplementation effects for health and clinical diseases.

Dr. Richard B. Kreider  
Dr. Jeffrey R. Stout  
 _Guest Editors_

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## Keywords

  * creatine
  * neurodegeneration
  * muscular diseases
  * metabolic dysfunction
  * aging
  * cognition
  * rehabilitation



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## Published Papers (28 papers) 

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## Research

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51 pages, 4247 KiB   [ __](/2072-6643/14/5/1035/pdf?version=1646206771 "Article PDF")

Open AccessArticle

[Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review](/2072-6643/14/5/1035)

by **Richard B. Kreider** , **Ralf Jäger** and **Martin Purpura**

_Nutrients_ **2022** , _14_(5), 1035; <https://doi.org/10.3390/nu14051035> \- 28 Feb 2022 

[Cited by 43](/2072-6643/14/5/1035#metrics) | Viewed by 26733 

**Abstract**

In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other "novel forms" of creatine that were being marketed at the time. This paper concluded that no other purported form  [...] Read more.

In 2011, we published a paper providing an overview about the bioavailability, efficacy, and regulatory status of creatine monohydrate (CrM), as well as other "novel forms" of creatine that were being marketed at the time. This paper concluded that no other purported form of creatine had been shown to be a more effective source of creatine than CrM, and that CrM was recognized by international regulatory authorities as safe for use in dietary supplements. Moreover, that most purported "forms" of creatine that were being marketed at the time were either less bioavailable, less effective, more expensive, and/or not sufficiently studied in terms of safety and/or efficacy. We also provided examples of several "forms" of creatine that were being marketed that were not bioavailable sources of creatine or less effective than CrM in comparative effectiveness trials. We had hoped that this paper would encourage supplement manufacturers to use CrM in dietary supplements given the overwhelming efficacy and safety profile. Alternatively, encourage them to conduct research to show their purported "form" of creatine was a bioavailable, effective, and safe source of creatine before making unsubstantiated claims of greater efficacy and/or safety than CrM. Unfortunately, unsupported misrepresentations about the effectiveness and safety of various "forms" of creatine have continued. The purpose of this critical review is to: (1) provide an overview of the physiochemical properties, bioavailability, and safety of CrM; (2) describe the data needed to substantiate claims that a "novel form" of creatine is a bioavailable, effective, and safe source of creatine; (3) examine whether other marketed sources of creatine are more effective sources of creatine than CrM; (4) provide an update about the regulatory status of CrM and other purported sources of creatine sold as dietary supplements; and (5) provide guidance regarding the type of research needed to validate that a purported "new form" of creatine is a bioavailable, effective and safe source of creatine for dietary supplements. Based on this analysis, we categorized forms of creatine that are being sold as dietary supplements as either having strong, some, or no evidence of bioavailability and safety. As will be seen, CrM continues to be the only source of creatine that has substantial evidence to support bioavailability, efficacy, and safety. Additionally, CrM is the source of creatine recommended explicitly by professional societies and organizations and approved for use in global markets as a dietary ingredient or food additive. [Full article](/2072-6643/14/5/1035)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-ag-550.jpg?1646288973 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g001-550.jpg?1646206879 "
                    <strong>Figure 1</strong><br/>
                                            <p>PRISMA flow chart.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g002-550.jpg?1646206879 "
                    <strong>Figure 2</strong><br/>
                                            <p>Changes in plasma creatine concentrations after administration of 5 g of creatine monohydrate \(CrM\) in solution \(<b>A</b>\) \[<a href="#B12-nutrients-14-01035" class="html-bibr">12</a>\]; water, 2 g of CrM administered in solution, or 408 g of slightly cooked meat containing 5.4 g of creatine \(<b>B</b>\) \[<a href="#B45-nutrients-14-01035" class="html-bibr">45</a>\]; or 2 g of CrM provided in solution, gel suspension, or in a hard candy lozenge \(<b>C</b>\) \[<a href="#B45-nutrients-14-01035" class="html-bibr">45</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g003-550.jpg?1646206879 "
                    <strong>Figure 3</strong><br/>
                                            <p>Chemical structure of creatine and creatine monohydrate.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g004-550.jpg?1646206878 "
                    <strong>Figure 4</strong><br/>
                                            <p>Conversion of creatine to creatinine \(<b>A</b>\) and influence of pH on creatine stability in solution \(<b>B</b>\). Creatine stability figure adapted from Howard and Harris \[<a href="#B55-nutrients-14-01035" class="html-bibr">55</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g005-550.jpg?1646206879 "
                    <strong>Figure 5</strong><br/>
                                            <p>Influence of pH on creatine stability in solution.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g006-550.jpg?1646206879 "
                    <strong>Figure 6</strong><br/>
                                            <p>Chemical structure of tri-creatine citrate and creatine pyruvate with plasma creatine changes after oral administration of equal molar doses of creatine monohydrate \(CrM\), creatine citrate \(CC\) and creatine pyruvate \(CPY\). Adapted from Jäger et al. \[<a href="#B63-nutrients-14-01035" class="html-bibr">63</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g007-550.jpg?1646206879 "
                    <strong>Figure 7</strong><br/>
                                            <p>Chemical structure of magnesium creatine.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g008-550.jpg?1646206878 "
                    <strong>Figure 8</strong><br/>
                                            <p>Chemical structure of creatine and creatine ethyl ester.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g009-550.jpg?1646206879 "
                    <strong>Figure 9</strong><br/>
                                            <p>Degradation of creatine ethyl ester to creatinine. Adapted from Jäger et al. \[<a href="#B25-nutrients-14-01035" class="html-bibr">25</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g010-550.jpg?1646206879 "
                    <strong>Figure 10</strong><br/>
                                            <p>Serum creatine \(<b>A</b>\), serum creatinine \(<b>B</b>\), and muscle creatine content \(<b>C</b>\). * Represents significant change from baseline. † in panel A indicates significantly higher serum creatine concentrations in CrM when compared to PLA \(<span class="html-italic">p</span> = 0.007\) and CEE \(<span class="html-italic">p</span> = 0.005\). † in panel B indicates serum creatinine in the CEE group was greater than PLA \(<span class="html-italic">p</span> = 0.001\) and CrM \(<span class="html-italic">p</span> = 0.001\). † in panel C shows the PLA group was significantly less than the CrM \(<span class="html-italic">p</span> = 0.026\) and CEE \(<span class="html-italic">p</span> = 0.041\) groups. Adapted from Spillane et al. \[<a href="#B27-nutrients-14-01035" class="html-bibr">27</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g011-550.jpg?1646206879 "
                    <strong>Figure 11</strong><br/>
                                            <p>Comparison of creatine monohydrate and creatine HCl structures.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g012-550.jpg?1646206879 "
                    <strong>Figure 12</strong><br/>
                                            <p>Chemical structure of creatine nitrate. \(<b>A</b>,<b>B</b>\) show 5 h area under the curve data after plasma creatine and plasma nitrate, respectively. \(<b>C</b>\) shows mean changes in muscle creatine content with 95% confidence intervals after 7 days of loading 4 doses/day and 21 days of ingesting 1 those/day. <sup>†</sup> Represents significant change from baseline, PLA and P represent placebo, CrM represents creatine monohydrate, and CrN represents creatine nitrate.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g013-550.jpg?1646206879 "
                    <strong>Figure 13</strong><br/>
                                            <p>Changes in muscle creatine content, fat-free mass, and 30 s cycling sprint performance after 7 and 28 days of CrM-Alk supplementation at 1.5 g/day recommended doses \(▲\), CrM-Alk supplementation of 20 g/day for 7 days and 5 g/day for 21 days \(◼\), or CrM supplementation of 20 g/day for 7 days and 5 g/day for 21 days \(●\). Adapted from Jagim et al. \[<a href="#B28-nutrients-14-01035" class="html-bibr">28</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g014-550.jpg?1646206878 "
                    <strong>Figure 14</strong><br/>
                                            <p>Changes in plasma creatine levels after oral ingestion of water, 5 mL of creatine serum \(CS\) purportedly providing 2.5 g of CrM, and 2.5 g of CrM in solution \(<b>A</b>\) \[<a href="#B26-nutrients-14-01035" class="html-bibr">26</a>\] and 5 days of 5 mL of CS purportedly providing 2.5 g of creatine \(CS-LD\), 5 mL of a flavored placebo \(PL-LD\), 8 × 5 mL of CS \(CS-HD\) purportedly providing 20 g/day of creatine, 8 × 5 mL of flavored placebo \(PL-HD\), or 4 × 5 g/day of CrM \(<b>B</b>\) \[<a href="#B26-nutrients-14-01035" class="html-bibr">26</a>\], Adapted from Harris et al. \[<a href="#B38-nutrients-14-01035" class="html-bibr">38</a>\] and Kreider et al. \[<a href="#B26-nutrients-14-01035" class="html-bibr">26</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g015-550.jpg?1646206879 "
                    <strong>Figure 15</strong><br/>
                                            <p>Comparison of creatine, creatine monohydrate, L-leucine, and creatyl-L-leucine chemical structures.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g016-550.jpg?1646206879 "
                    <strong>Figure 16</strong><br/>
                                            <p>Blood, muscle, and brain creatine content in response to rats fed a control diet, 4.0 g/kg/day of creatine monohydrate \(CrM\), or 6.56 g/kg/day of creatyl-L-Leucine \(CLL\) for 7 days. \(<b>A</b>\) presents arterial plasma creatine concentration, \(<b>B</b>\) presents portal vein creatine concentration, \(<b>C</b>\) presents muscle creatine content, and \(<b>D</b>\) presents brain creatine content data for each group. Data are means ± standard deviations. **** = <span class="html-italic">p</span> &lt; 0.0001, *** = <span class="html-italic">p</span> &lt; 0.001, ** = <span class="html-italic">p</span> &lt; 0.01, * <span class="html-italic">p</span> &lt; 0.05, ns = not statistically significant between groups identified in brackets. Adapted from da Silva \[<a href="#B221-nutrients-14-01035" class="html-bibr">221</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-01035/article_deploy/html/images/nutrients-14-01035-g017-550.jpg?1646206879 "
                    <strong>Figure 17</strong><br/>
                                            <p>Chemical structure of Creatinol-O-Phosphate.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/5/1035'>Full article</a></strong>
                                        ")

8 pages, 6887 KiB   [ __](/2072-6643/14/3/701/pdf?version=1644298817 "Article PDF")

Open AccessArticle

[The Dietary Supplement Creatyl-l-Leucine Does Not Bioaccumulate in Muscle, Brain or Plasma and Is Not a Significant Bioavailable Source of Creatine](/2072-6643/14/3/701)

by **Robin P. da Silva**

_Nutrients_ **2022** , _14_(3), 701; <https://doi.org/10.3390/nu14030701> \- 8 Feb 2022 

[Cited by 3](/2072-6643/14/3/701#metrics) | Viewed by 5124 

**Abstract**

Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. Dietary supplementation with relatively  [...] Read more.

Creatine is an important energy metabolite that is concentrated in tissues such as the muscles and brain. Creatine is reversibly converted to creatine phosphate through a reaction with ATP or ADP, which is catalyzed by the enzyme creatine kinase. Dietary supplementation with relatively large amounts of creatine monohydrate has been proven as an effective sports supplement that can enhances athletic performance during acute high-energy demand physical activity. Some side effects have been reported with creatine monohydrate supplementation, which have stimulated research into new potential molecules that could be used as supplements to potentially provide bioavailable creatine. Recently, a popular supplement, creatyl-l-leucine, has been proposed as a potential dietary ingredient that may potentially provide bioavailable creatine. This study tests whether creatyl-l-leucine is a bioavailable compound and determines whether it can furnish creatine as a dietary supplement. Rats were deprived of dietary creatine for a period of two weeks and then given one of three treatments: a control AIN-93G creatine-free diet, AIN-93G supplemented with creatine monohydrate or AIN-93G with an equimolar amount of creatyl-l-leucine supplement in the diet for one week. When compared to the control and the creatine monohydrate-supplemented diet, creatyl-l-leucine supplementation resulted in no bioaccumulation of either creatyl-l-leucine or creatine in tissue. [Full article](/2072-6643/14/3/701)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-14-00701/article_deploy/html/images/nutrients-14-00701-g001-550.jpg?1644298910 "
                    <strong>Figure 1</strong><br/>
                                            <p>Chemical structures of \(<b>A</b>\) creatyl-<span class="html-small-caps">l</span>-leucine and \(<b>B</b>\) creatine.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/701'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00701/article_deploy/html/images/nutrients-14-00701-g002-550.jpg?1644298910 "
                    <strong>Figure 2</strong><br/>
                                            <p>Body weight over the course of the feeding trial. Open circles represent weights for rats fed creatine-free AIN-93G diet for the entire 21 days; open triangles represent weights for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.4% \(<span class="html-italic">w</span>/<span class="html-italic">w</span>\) creatine monohydrate for the remaining 7 days; black circles represent weights for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.656% \(<span class="html-italic">w</span>/<span class="html-italic">w</span>\) creatyl-<span class="html-small-caps">l</span>-leucine \(CLL\) for the remaining 7 days. Values are presented as the mean ± one standard deviation, n = 8 per group.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/701'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00701/article_deploy/html/images/nutrients-14-00701-g003-550.jpg?1644298910 "
                    <strong>Figure 3</strong><br/>
                                            <p>Food intake for all groups. Panel \(<b>A</b>\) Data for all days of experiment and panel \(<b>B</b>\) expanded data for days 15–21. Open circles represent the average daily food intake for rats fed creatine-free AIN-93G diet for the entire 21 days; open triangles represent average daily food intake for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.4% \(<span class="html-italic">w</span>/<span class="html-italic">w</span>\) creatine monohydrate for days 15–21; black circles represent average daily food intake for rats fed creatine-free diet for 14 days and then switched to AIN-93G diet supplemented with 0.656% \(<span class="html-italic">w</span>/<span class="html-italic">w</span>\) creatyl-<span class="html-small-caps">l</span>-leucine \(CLL\) for days 15–21. Values are presented as the mean ± one standard deviation, n = 8 per group.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/701'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00701/article_deploy/html/images/nutrients-14-00701-g004-550.jpg?1644298910 "
                    <strong>Figure 4</strong><br/>
                                            <p>Plasma concentrations of creatine and guanidinoacetate. Panel \(<b>A</b>\) arterial plasma concentration of creatine; panel \(<b>B</b>\) portal venous plasma concentration of creatine; panel \(<b>C</b>\) arterial plasma concentration of guanidinoacetate; panel \(<b>D</b>\) portal venous concentration of guanidinoacetate. The open bar represents rats fed creatine-free diet \(CON\), light gray bar represents rats fed 0.4% <span class="html-italic">w</span>/<span class="html-italic">w</span> creatine monohydrate supplemented diet, dark gray bar represents rats fed 0.656% CLL supplemented diet. Values are presented as the mean ± one standard deviation, n = 8 per group. Asterisks indicate significance by <span class="html-italic">p</span>-value; <span class="html-italic">p</span> &lt; 0.0001 = ****, <span class="html-italic">p</span> &lt; 0.001 = ***, <span class="html-italic">p</span> &lt; 0.01 = **, ns = not significant.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/701'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00701/article_deploy/html/images/nutrients-14-00701-g005-550.jpg?1644298910 "
                    <strong>Figure 5</strong><br/>
                                            <p>Muscle and brain creatine content. Panel \(<b>A</b>\) Creatine content of quadricep muscle; panel \(<b>B</b>\); creatine content of whole brain. The open bar represents rats fed creatine-free diet \(CON\), light gray bar represents rats fed 0.4% <span class="html-italic">w</span>/<span class="html-italic">w</span> creatine monohydrate-supplemented diet, dark gray bar represents rats fed 0.656% CLL supplemented diet. Values are presented as the mean ± one standard deviation, n = 8 per group. Asterisks indicate significance by <span class="html-italic">p</span>-value; <span class="html-italic">p</span> &lt; 0.01 = **, <span class="html-italic">p</span> &lt; 0.05 = *, ns = not significant.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/701'>Full article</a></strong>
                                        ")

_attachment_

Supplementary material:   
[ Supplementary File 1 (ZIP, 365 KiB) ](/2072-6643/14/3/583/s1?version=1643378096)  


15 pages, 2285 KiB   [ __](/2072-6643/14/3/583/pdf?version=1643378095 "Article PDF")

Open AccessArticle

[Supplementing Soy-Based Diet with Creatine in Rats: Implications for Cardiac Cell Signaling and Response to Doxorubicin](/2072-6643/14/3/583)

by **Laurence Kay** , **Lucia Potenza** , **Isabelle Hininger-Favier** , **Hubert Roth** , **Stéphane Attia** , **Cindy Tellier** , **Christian Zuppinger** , **Cinzia Calcabrini** , **Piero Sestili** , **Theo Wallimann** , **Uwe Schlattner** and **Malgorzata Tokarska-Schlattner**

_Nutrients_ **2022** , _14_(3), 583; <https://doi.org/10.3390/nu14030583> \- 28 Jan 2022 

[Cited by 4](/2072-6643/14/3/583#metrics) | Viewed by 3750 

**Abstract**

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular  [...] Read more.

Nutritional habits can have a significant impact on cardiovascular health and disease. This may also apply to cardiotoxicity caused as a frequent side effect of chemotherapeutic drugs, such as doxorubicin (DXR). The aim of this work was to analyze if diet, in particular creatine (Cr) supplementation, can modulate cardiac biochemical (energy status, oxidative damage and antioxidant capacity, DNA integrity, cell signaling) and functional parameters at baseline and upon DXR treatment. Here, male Wistar rats were fed for 4 weeks with either standard rodent diet (NORMAL), soy-based diet (SOY), or Cr-supplemented soy-based diet (SOY + Cr). Hearts were either freeze-clamped in situ or following ex vivo Langendorff perfusion without or with 25 μM DXR and after recording cardiac function. The diets had distinct cardiac effects. Soy-based diet (SOY vs. NORMAL) did not alter cardiac performance but increased phosphorylation of acetyl-CoA carboxylase (ACC), indicating activation of rather pro-catabolic AMP-activated protein kinase (AMPK) signaling, consistent with increased ADP/ATP ratios and lower lipid peroxidation. Creatine addition to the soy-based diet (SOY + Cr vs. SOY) slightly increased left ventricular developed pressure (LVDP) and contractility dp/dt, as measured at baseline in perfused heart, and resulted in activation of the rather pro-anabolic protein kinases Akt and ERK. Challenging perfused heart with DXR, as analyzed across all nutritional regimens, deteriorated most cardiac functional parameters and also altered activation of the AMPK, ERK, and Akt signaling pathways. Despite partial reprogramming of cell signaling and metabolism in the rat heart, diet did not modify the functional response to supraclinical DXR concentrations in the used acute cardiotoxicity model. However, the long-term effect of these diets on cardiac sensitivity to chronic and clinically relevant DXR doses remains to be established. [Full article](/2072-6643/14/3/583)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-ag-550.jpg?1643378187 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g001-550.jpg?1643378187 "
                    <strong>Figure 1</strong><br/>
                                            <p>Scheme of the experimental procedure \(for details, see Material and Methods\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g002-550.jpg?1643378187 "
                    <strong>Figure 2</strong><br/>
                                            <p>Heart function: effect of diet and DXR. Hemodynamic parameters: left ventricular developed pressure \(LVDP\), end-diastolic pressure \(EDP\), dp/dt, −dp/dt, heart rate \(HR\), and rate pressure product \(RPP\) measured in Langendorff perfused hearts after 30 min of stabilization \(<b>A</b>\) or after 30 min of stabilization followed by an additional 80 min of perfusion \(<b>B</b>\) without or with 25 μM DXR \(empty or hatched bars, respectively\). EDP values are given only in \(<b>B</b>\), as during the stabilization period shown in \(<b>A</b>\), EDP was adjusted to 5 mm Hg and thereafter the volume of the balloon rest unchanged. Statistical analysis with linear regression followed by the Bonferroni test for pairwise comparisons. For −dp/dt, HR, RPP in \(<b>A</b>\), and HR in \(<b>B</b>\), there are no statistically significant differences between groups. Mean ± SEM, <span class="html-italic">n</span> = 11–28 \(<b>A</b>\), <span class="html-italic">n</span> = 4–14 \(<b>B</b>\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g003-550.jpg?1643378187 "
                    <strong>Figure 3</strong><br/>
                                            <p>Energy metabolite levels: effect of diet and DXR. PCr, free Cr, total Cr, ATP, ADP/ATP, and AMP/ATP ratios in hearts freeze-clamped in situ immediately after thoracotomy \(<b>A</b>\) or following ex vivo Langendorff perfusion \(<b>B</b>\) without or with 25 μM DXR \(empty or hatched bars, respectively\). Statistical analysis with linear regression followed by the Bonferroni test for pairwise comparisons. For PCr, ATP, and AMP/ATP in \(<b>A</b>\) and PCr and ADP/ATP in \(<b>B</b>\), there are no statistically significant differences between groups. Mean ± SEM, <span class="html-italic">n</span> = 3–6 \(<b>A</b>\), <span class="html-italic">n</span> = 4–16 \(<b>B</b>\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g004-550.jpg?1643378187 "
                    <strong>Figure 4</strong><br/>
                                            <p>Activation of signaling pathways: effect of diet and DXR. Activation of cardiac pro-survival signaling pathways \(AMPK, Akt, ERK\) probed by immunoblot in total homogenates of hearts freeze-clamped in situ immediately after thoracotomy \(<b>A</b>\) or following ex vivo Langendorff perfusion \(<b>B</b>\) without or with 25 μM DXR. The P-ACC/ACC ratio and phosphorylated Akt substrates are a readout for the activation of the AMPK and Akt pathways, respectively. The quantification of the bands is given in the right panel; in \(<b>B</b>\), empty or hatched bars correspond to perfusion without or with 25 μM DXR, respectively. For each protein, all signals originate from the same blot. Total protein or tubulin signals were used for normalization. Statistical analysis with one-way \(<b>A</b>\) or two-way \(<b>B</b>\) ANOVA followed by the Student–Newman–Keuls test for pairwise comparisons. For P-AMPK/AMPK in \(<b>A</b>\), there is no statistically significant difference between groups. Mean ± SD, <span class="html-italic">n</span> = 3–5.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g005-550.jpg?1643378187 "
                    <strong>Figure 5</strong><br/>
                                            <p>Oxidative/antioxidant status: effect of diet and DXR. Reduced thiols, peroxidized lipids \(TBARS\), and total antioxidant power \(FRAP\) measured in hearts freeze-clamped in situ immediately after thoracotomy \(<b>A</b>\) or following ex vivo Langendorff perfusion \(<b>B</b>\) without or with 25 μM DXR \(empty or hatched bars, respectively\). Statistical analysis with one-way \(<b>A</b>\) or two-way \(<b>B</b>\) ANOVA followed by the Student–Newman–Keuls test for pairwise comparisons. For thiols, TBARS in \(<b>A</b>\) and thiols in \(<b>B</b>\), there are no statistically significant differences between groups. Mean ± SEM, <span class="html-italic">n</span> = 5–6 \(<b>A</b>\), <span class="html-italic">n</span> = 4–7 \(<b>B</b>\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00583/article_deploy/html/images/nutrients-14-00583-g006-550.jpg?1643378187 "
                    <strong>Figure 6</strong><br/>
                                            <p>DNA integrity: effect of diet and DXR. Integrity of nuclear and mitochondrial DNA measured in hearts freeze-clamped in situ immediately after thoracotomy \(<b>A</b>\) or following ex vivo Langendorff perfusion \(<b>B</b>\). The bars in \(<b>B</b>\) represent the ratio of amplification values of DXR-perfused hearts to controls \(perfusion without DXR\) and are expressed as a percent. Statistical analysis with one-way ANOVA. For any parameter, there is no statistically significant difference between groups. Mean ± SD, <span class="html-italic">n</span> = 4–5.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/583'>Full article</a></strong>
                                        ")

_attachment_

Supplementary material:   
[ Supplementary File 1 (ZIP, 903 KiB) ](/2072-6643/13/8/2521/s1?version=1627055222)  


25 pages, 3622 KiB   [ __](/2072-6643/13/8/2521/pdf?version=1627281635 "Article PDF")

Open AccessArticle

[A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation](/2072-6643/13/8/2521)

by **Diego A. Bonilla** , **Yurany Moreno** , **Eric S. Rawson** , **Diego A. Forero** , **Jeffrey R. Stout** , **Chad M. Kerksick** , **Michael D. Roberts** and **Richard B. Kreider**

_Nutrients_ **2021** , _13_(8), 2521; <https://doi.org/10.3390/nu13082521> \- 23 Jul 2021 

[Cited by 7](/2072-6643/13/8/2521#metrics) | Viewed by 5778 

**Abstract**

Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis  [...] Read more.

Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms. [Full article](/2072-6643/13/8/2521)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-ag-550.jpg?1627281756 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g001-550.jpg?1627281756 "
                    <strong>Figure 1</strong><br/>
                                            <p>PRISMA flow diagram.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g002-550.jpg?1627281756 "
                    <strong>Figure 2</strong><br/>
                                            <p>Convergent analysis of the differentially expressed genes obtained from the three datasets: \(<b>A</b>\) Venn diagram comparing differentially expressed genes identified in the included datasets \(adjusted <span class="html-italic">p</span> &lt; 0.05\); \(<b>B</b>\) list of genes derived from the convergent functional genomics analysis in human and mouse models. Hs: <span class="html-italic">Homo sapiens</span>; Mm: <span class="html-italic">Mus musculus</span>.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g003a-550.jpg?1627281756 "
                    <strong>Figure 3</strong><br/>
                                            <p>Upstream regulatory pathway analysis of the 35 selected differentially expressed genes: \(<b>A</b>\). transcription factor enrichment analysis; \(<b>B</b>\) protein–protein interaction expansion; \(<b>C</b>\) kinase enrichment analysis; \(<b>D</b>\) eXpression2Kinases network. Figures were obtained from the X2K Web \(<a href="https://amp.pharm.mssm.edu/X2K/" target="_blank">https://amp.pharm.mssm.edu/X2K/</a>, accessed on 12 May 2021\) after running the upstream pathway analysis of the selected genes as the input gene list.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g003b-550.jpg?1627281756 "
                    <strong>Figure 3 Cont.</strong><br/>
                                            <p>Upstream regulatory pathway analysis of the 35 selected differentially expressed genes: \(<b>A</b>\). transcription factor enrichment analysis; \(<b>B</b>\) protein–protein interaction expansion; \(<b>C</b>\) kinase enrichment analysis; \(<b>D</b>\) eXpression2Kinases network. Figures were obtained from the X2K Web \(<a href="https://amp.pharm.mssm.edu/X2K/" target="_blank">https://amp.pharm.mssm.edu/X2K/</a>, accessed on 12 May 2021\) after running the upstream pathway analysis of the selected genes as the input gene list.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g004-550.jpg?1627281756 "
                    <strong>Figure 4</strong><br/>
                                            <p>Bioinformatics- and knowledge-based pathway reconstruction after Cr supplementation. This is a representation of pathways interactions based on the results of our enrichment analysis of differentially expressed genes after increasing cellular Cr concentration and the available experimental evidence. This functional network follows the ‘bio-logic’ \(integration of bottom-up and top-down directions\) of the genotype–outcome interaction. MAPK activation can occur via osmosensing pathways that activate Ras/Raf \(e.g., S1P/SPHK1\) and mechanosensing pathways that involve mechanical and energy optimization of the cytoskeleton \(e.g., Four-and-a-Half Lim 2 is an important mechanosensor that triggers hypertrophy in response to strain and also docks key metabolic enzymes involved in the energy transduction process, such as M-CK, adenylate kinase, and phosphofructokinase\). Several subunits of the protein complexes and the architecture of the cytoskeleton are not depicted for readability. We cautiously suggest two dose–response functional pathways for the regulation of the Cr uptake: a kinase-driven mechanism as a result of the initial Cr-enriched environment, which is more related to the anterograde trafficking via endolysosome-specific phosphoinositide compounds \(1\); and a ubiquitin-driven mechanism that controls the excessive Cr uptake, which is more related to the retrograde trafficking via clathrin-dependent and clathrin-independent processes \(2\). Interlinking protein filaments of the cytoskeleton are represented with lighter-colored lines in the background. See the sections of the manuscript for rationale, citations, and more abbreviations. Dashed arrows represent multiple steps. AMPK: AMP-activated protein kinase; CK: creatine kinase; GASP-1: growth and differentiation factor \(GDF\)-associated serum protein-1; GDP: guanosine diphosphate; GH: growth hormone; GLUT: glucose transporter; GRB2: growth factor receptor-bound protein 2; GTP: guanosine triphosphate; IGF-1: insulin-like growth factor-1; LST8: target of rapamycin complex subunit LST8; MRFs: myogenic regulatory factors; Nedd4-2: E3 ubiquitin–protein ligase NEDD4-like; OSR1: oxidative-stress-responsive kinase 1; PDK1: phosphoinositide-dependent kinase-1; PFK: phosphofructokinase; PI\(3,5\)P<sub>2</sub>: phosphatidylinositol 3,5-bisphosphate; PIKfyve: 1-phosphatidylinositol 3-phosphate 5-kinase; PI3K: phosphoinositide 3-kinase; PIP<sub>3</sub>: phosphatidylinositol \(3,4,5\)-trisphosphate; PK: pyruvate kinase; SGK: serum- and glucocorticoid-regulated kinase; SPAK: SPS1-related proline–alanine-rich kinase; RACK1: receptor for activated C kinase 1; RTK: receptor tyrosine kinases; TFs: transcription factors. Source: created by the authors \(D.A.B.\) with BioRender—<a href="https://biorender.com/" target="_blank">https://biorender.com/</a> \(accessed on 10 May 2021\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02521/article_deploy/html/images/nutrients-13-02521-g0A1-550.jpg?1627281756 "
                    <strong>Figure A1</strong><br/>
                                            <p>Effects of ten days of CrM supplementation in healthy young men \(with no changes in their dietary intake\) on protein kinase content using the Kinetworks KPKS 1.0 Protein Kinase screen. PSTK = protein–serine/threonine kinase; PTYK = protein–threonine/tyrosine kinase; PYK = protein–tyrosine kinase; PTK = protein–threonine kinase. Significant increases \(red; <span class="html-italic">p</span> &lt; 0.05\), trends for increases \(green; <span class="html-italic">p</span> &lt; 0.09\), and no change \(grey\) in protein content with CrM supplementation vs. placebo are indicated. Reproduced from Safdar et al. \(2008\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2521'>Full article</a></strong>
                                        ")

13 pages, 1833 KiB   [ __](/2072-6643/13/7/2406/pdf?version=1626315126 "Article PDF")

Open AccessArticle

[Creatine Monohydrate Supplementation Increases White Adipose Tissue Mitochondrial Markers in Male and Female Rats in a Depot Specific Manner](/2072-6643/13/7/2406)

by **Chantal R. Ryan** , **Michael S. Finch** , **Tyler C. Dunham** , **Jensen E. Murphy** , **Brian D. Roy** and **Rebecca E. K. MacPherson**

_Nutrients_ **2021** , _13_(7), 2406; <https://doi.org/10.3390/nu13072406> \- 14 Jul 2021 

[Cited by 5](/2072-6643/13/7/2406#metrics) | Viewed by 4744 

**Abstract**

White adipose tissue (WAT) is a dynamic endocrine organ that can play a significant role in thermoregulation. WAT has the capacity to adopt structural and functional characteristics of the more metabolically active brown adipose tissue (BAT) and contribute to non-shivering thermogenesis under specific  [...] Read more.

White adipose tissue (WAT) is a dynamic endocrine organ that can play a significant role in thermoregulation. WAT has the capacity to adopt structural and functional characteristics of the more metabolically active brown adipose tissue (BAT) and contribute to non-shivering thermogenesis under specific stimuli. Non-shivering thermogenesis was previously thought to be uncoupling protein 1 (UCP1)-dependent however, recent evidence suggests that UCP1-independent mechanisms of thermogenesis exist. Namely, futile creatine cycling has been identified as a contributor to WAT thermogenesis. The purpose of this study was to examine the efficacy of creatine supplementation to alter mitochondrial markers as well as adipocyte size and multilocularity in inguinal (iWAT), gonadal (gWAT), and BAT. Thirty-two male and female Sprague-Dawley rats were treated with varying doses (0 g/L, 2.5 g/L, 5 g/L, and 10 g/L) of creatine monohydrate for 8 weeks. We demonstrate that mitochondrial markers respond in a sex and depot specific manner. In iWAT, female rats displayed significant increases in COXIV, PDH-E1alpha, and cytochrome C protein content. Male rats exhibited gWAT specific increases in COXIV and PDH-E1alpha protein content. This study supports creatine supplementation as a potential method of UCP1-independant thermogenesis and highlights the importance of taking a sex-specific approach when examining the efficacy of browning therapeutics in future research. [Full article](/2072-6643/13/7/2406)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-02406/article_deploy/html/images/nutrients-13-02406-g001-550.jpg?1626315208 "
                    <strong>Figure 1</strong><br/>
                                            <p>Subcutaneous inguinal white adipose tissue \(iWAT\) mitochondrial protein content and morphology. \(<b>A</b>\) Quantified Western blot data for iWAT protein content of COXIV, PDH-E1α, Cytochrome C \(Cyto C\), citrate synthase \(CS\), PGC-1α, and uncoupling protein-1 \(UCP1\) for control male and female rats. \(<b>B</b>\) Quantified Western blot data for mitochondrial proteins across creatine supplemented groups and representative Western blot images. \(<b>C</b>\) UCP-1 content in male and female rats across creatine supplemented groups. \(<b>D</b>\). Representative images of H&amp;E stained slides. Scale bar on H&amp;E representative image represents 100 μm. Data were analyzed by ANOVA and are presented as mean ± SEM, * denotes significantly different from control group, <span class="html-italic">p</span> &lt; 0.05.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2406'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02406/article_deploy/html/images/nutrients-13-02406-g002-550.jpg?1626315208 "
                    <strong>Figure 2</strong><br/>
                                            <p>Visceral gonadal white adipose tissue \(gWAT\) mitochondrial protein content and morphology. \(<b>A</b>\) Quantified Western blot data for gWAT protein content of COXIV, PDH-E1α, Cytochrome C \(Cyto C\), citrate synthase \(CS\), PGC-1α, and uncoupling protein-1 \(UCP1\) for control male and female rats. \(<b>B</b>\) Quantified Western blot data for mitochondrial proteins across creatine supplemented groups and representative Western blot images. \(<b>C</b>\) Representative images of H&amp;E stained slides. Scale bar on H&amp;E representative image represents 100 μm. Data were analyzed by ANOVA and are presented as mean ± SEM, * denotes significantly different from control group, <span class="html-italic">p</span> &lt; 0.05.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2406'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02406/article_deploy/html/images/nutrients-13-02406-g003-550.jpg?1626315208 "
                    <strong>Figure 3</strong><br/>
                                            <p>Brown adipose tissue \(BAT\) mitochondrial protein content and morphology. \(<b>A</b>\) Quantified Western blot data for BAT protein content of COXIV, PDH-E1α, Cytochrome C \(Cyto C\), citrate synthase \(CS\), PGC-1α, and uncoupling protein-1 \(UCP1\) for control male and female rats. \(<b>B</b>\) Quantified Western blot data for mitochondrial proteins across creatine supplemented groups and representative Western blot images. \(<b>C</b>\) UCP-1 content in male and female rats across creatine supplemented groups. \(<b>D</b>\) Representative images of H&amp;E stained slides. Scale bar on H&amp;E representative image represents 100 μm. Data were analyzed by ANOVA and are presented as mean ± SEM, denotes significantly different from control group, <span class="html-italic">p</span> &lt; 0.05.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2406'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02406/article_deploy/html/images/nutrients-13-02406-g004-550.jpg?1626315208 "
                    <strong>Figure 4</strong><br/>
                                            <p>Adipose tissue markers of creatine uptake and metabolism. \(<b>A</b>\) Adipose tissue depot GAMT protein content in female \(left\) and male \(right\) rats. \(<b>B</b>\) Creatine kinase B content. \(<b>C</b>\) Slc6A8 mRNA expression. \(<b>D</b>\) Creatine content. Data were analyzed by ANOVA and are presented as mean ± SEM, * denotes significantly different from control group, <span class="html-italic">p</span> &lt; 0.05.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2406'>Full article</a></strong>
                                        ")

18 pages, 4251 KiB   [ __](/2072-6643/13/7/2303/pdf?version=1625543504 "Article PDF")

Open AccessArticle

[Creatine Enhances the Effects of Cluster-Set Resistance Training on Lower-Limb Body Composition and Strength in Resistance-Trained Men: A Pilot Study](/2072-6643/13/7/2303)

by **Diego A. Bonilla** , **Richard B. Kreider** , **Jorge L. Petro** , **Ramón Romance** , **Manuel García-Sillero** , **Javier Benítez-Porres** and **Salvador Vargas-Molina**

_Nutrients_ **2021** , _13_(7), 2303; <https://doi.org/10.3390/nu13072303> \- 4 Jul 2021 

[Cited by 15](/2072-6643/13/7/2303#metrics) | Viewed by 8447 

**Abstract**

Creatine monohydrate (CrM) supplementation has been shown to improve body composition and muscle strength when combined with resistance training (RT); however, no study has evaluated the combination of this nutritional strategy with cluster-set resistance training (CS-RT). The purpose of this pilot study was  [...] Read more.

Creatine monohydrate (CrM) supplementation has been shown to improve body composition and muscle strength when combined with resistance training (RT); however, no study has evaluated the combination of this nutritional strategy with cluster-set resistance training (CS-RT). The purpose of this pilot study was to evaluate the effects of CrM supplementation during a high-protein diet and a CS-RT program on lower-limb fat-free mass (LL-FFM) and muscular strength. Twenty-three resistance-trained men (>2 years of training experience, 26.6 ± 8.1 years, 176.3 ± 6.8 cm, 75.6 ± 8.9 kg) participated in this study. Subjects were randomly allocated to a CS-RT+CrM (_n_ = 8), a CS-RT (_n_ = 8), or a control group (_n_ = 7). The CS-RT+CrM group followed a CrM supplementation protocol with 0.1 g·kg−1·day−1 over eight weeks. Two sessions per week of lower-limb CS-RT were performed. LL-FFM corrected for fat-free adipose tissue (dual-energy X-ray absorptiometry) and muscle strength (back squat 1 repetition maximum (SQ-1RM) and countermovement jump (CMJ)) were measured pre- and post-intervention. Significant improvements were found in whole-body fat mass, fat percentage, LL-fat mass, LL-FFM, and SQ-1RM in the CS-RT+CrM and CS-RT groups; however, larger effect sizes were obtained in the CS-RT+CrM group regarding whole body FFM (0.64 versus 0.16), lower-limb FFM (0.62 versus 0.18), and SQ-1RM (1.23 versus 0.75) when compared to the CS-RT group. CMJ showed a significant improvement in the CS-RT+CrM group with no significant changes in CS-RT or control groups. No significant differences were found between groups. Eight weeks of CrM supplementation plus a high-protein diet during a CS-RT program has a higher clinical meaningfulness on lower-limb body composition and strength-related variables in trained males than CS-RT alone. Further research might study the potential health and therapeutic effects of this nutrition and exercise strategy. [Full article](/2072-6643/13/7/2303)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g001-550.jpg?1625543612 "
                    <strong>Figure 1</strong><br/>
                                            <p>Experimental design of the study. CMJ: countermovement jump; CrM: creatine monohydrate; CS-RT: cluster-set resistance training; LL-DXA: lower-limb assessment with dual-energy X-ray absorptiometry; SQ-1RM: 1 repetition maximum for the back squat.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g002-550.jpg?1625543612 "
                    <strong>Figure 2</strong><br/>
                                            <p>CONSORT flow diagram.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g003a-550.jpg?1625543612 "
                    <strong>Figure 3</strong><br/>
                                            <p>Estimation plots showing pre- and post-intervention values on analyzed variables. Paired data from CS-RT+CrM \(left\), CS-RT \(middle\), and control \(right\) groups are shown as small circles joined by blue lines. The differences between the initial \(Week 0\) and final \(Week 8\) means are plotted on a floating difference axis whose zero is aligned with the pre-test mean. The filled pink triangle marks the difference on that axis and the 95% CI on that difference is displayed. The differences are shown as open triangles on the difference axis. FFM and LL-FFM were corrected for fat-free adipose tissue. BMI, body mass index; CI, confidence interval; CMJ, countermovement jump; CrM, creatine monohydrate; CS-RT, cluster-set resistance training; FFAT, fat-free adipose tissue; FFM, fat-free mass; FM, fat mass; LL-FFAT; lower-limb fat-free adipose tissue; LL-FFM; lower-limb fat-free mass; LL-FM; lower-limb fat mass; LL-mass, lower-limb mass; SQ-1RM, 1 repetition maximum for the back squat.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g003b-550.jpg?1625543612 "
                    <strong>Figure 3 Cont.</strong><br/>
                                            <p>Estimation plots showing pre- and post-intervention values on analyzed variables. Paired data from CS-RT+CrM \(left\), CS-RT \(middle\), and control \(right\) groups are shown as small circles joined by blue lines. The differences between the initial \(Week 0\) and final \(Week 8\) means are plotted on a floating difference axis whose zero is aligned with the pre-test mean. The filled pink triangle marks the difference on that axis and the 95% CI on that difference is displayed. The differences are shown as open triangles on the difference axis. FFM and LL-FFM were corrected for fat-free adipose tissue. BMI, body mass index; CI, confidence interval; CMJ, countermovement jump; CrM, creatine monohydrate; CS-RT, cluster-set resistance training; FFAT, fat-free adipose tissue; FFM, fat-free mass; FM, fat mass; LL-FFAT; lower-limb fat-free adipose tissue; LL-FFM; lower-limb fat-free mass; LL-FM; lower-limb fat mass; LL-mass, lower-limb mass; SQ-1RM, 1 repetition maximum for the back squat.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g004a-550.jpg?1625543612 "
                    <strong>Figure 4</strong><br/>
                                            <p>Difference-in-difference estimation plots for all variables. This graphic shows the difference \(Δ = Week 8–Week 0\) of the differences, which is the calculation of the group means: CS-RT+CrM \(Δ<sub>1</sub>\), CS-RT \(Δ<sub>2</sub>\), and control \(Δ<sub>3</sub>\) groups on lower-limb body composition and strength-related variables. The effect chosen for examination is displayed as the triangle, with its 95% CI, against a floating different axis.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02303/article_deploy/html/images/nutrients-13-02303-g004b-550.jpg?1625543612 "
                    <strong>Figure 4 Cont.</strong><br/>
                                            <p>Difference-in-difference estimation plots for all variables. This graphic shows the difference \(Δ = Week 8–Week 0\) of the differences, which is the calculation of the group means: CS-RT+CrM \(Δ<sub>1</sub>\), CS-RT \(Δ<sub>2</sub>\), and control \(Δ<sub>3</sub>\) groups on lower-limb body composition and strength-related variables. The effect chosen for examination is displayed as the triangle, with its 95% CI, against a floating different axis.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/7/2303'>Full article</a></strong>
                                        ")

9 pages, 602 KiB   [ __](/2072-6643/13/3/1027/pdf?version=1616659984 "Article PDF")

Open AccessArticle

[Relationship between Dietary Creatine and Growth Indicators in Children and Adolescents Aged 2–19 Years: A Cross-Sectional Study](/2072-6643/13/3/1027)

by **Darinka Korovljev** , **Valdemar Stajer** and **Sergej M. Ostojic**

_Nutrients_ **2021** , _13_(3), 1027; <https://doi.org/10.3390/nu13031027> \- 23 Mar 2021 

[Cited by 11](/2072-6643/13/3/1027#metrics) | Viewed by 7311 

**Abstract**

A possible role of dietary creatine for ensuring proper growth and development remains unknown. The main aim of this cross-sectional study was to quantify the amount of creatine consumed through regular diet among U.S. children and adolescents aged 2 to 19 years and  [...] Read more.

A possible role of dietary creatine for ensuring proper growth and development remains unknown. The main aim of this cross-sectional study was to quantify the amount of creatine consumed through regular diet among U.S. children and adolescents aged 2 to 19 years and investigate the relationship between creatine intake and growth indicators, using data from the 2001–2002 National Health and Nutrition Examination Survey (NHANES). We included data for NHANES 2001–2002 respondents (4291 participants, 2133 boys and 2158 girls) aged 2 to 19 years at the time of screening, who provided valid dietary information and examination measures (standing height and weight). Individual values for total grams of creatine consumed per day for each participant were computed using the average amount of creatine (3.88 g/kg) across all sources of meat-based foods. All participants were categorized for height-for-age and BMI-for-age categories. The average daily intake of creatine across the whole sample was 1.07 ± 1.07 g (95% CI, from 1.04 to 1.10). Height, weight, and BMI were significantly different across creatine quartiles (_p_ < 0.001), with all measures significantly higher in the 4th quartile of creatine intake (≥1.5 g/day) than those in other quartiles (_p_ < 0.05). The participants from the 3rd quartile of creatine intake (0.84–1.49 g/day) were significantly different from others with respect to having lower rates of normal stature and higher rates of tall stature (_p_ < 0.05). Each additional 0.1 g of creatine consumed per day increases height by 0.60 cm (simple model) or 0.30 cm (adjusted model). The daily intake of creatine from a regular diet in taller children and adolescents was higher than in shorter peers aged 2–19 years. Future research has to monitor temporal changes in growth and dietary creatine and validate our findings in interventional studies across pediatric populations. [Full article](/2072-6643/13/3/1027)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01027/article_deploy/html/images/nutrients-13-01027-g001-550.jpg?1616660098 "
                    <strong>Figure 1</strong><br/>
                                            <p>Dietary intake of creatine \(g/day\) across stature-for-age and BMI-for-age categories.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/1027'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01027/article_deploy/html/images/nutrients-13-01027-g002-550.jpg?1616660098 "
                    <strong>Figure 2</strong><br/>
                                            <p>Dietary intake of creatine \(g/day\) across stature-for-age. Creatine intake across quartiles was 0.00–0.28 g \(Q1\), 0.28–0.83 g \(Q2\), 0.84–1.49 g \(Q3\), and 1.50–8.28 g \(Q4\). Asterisk \(*\) indicates a significant difference at <span class="html-italic">p</span> &lt; 0.05 between quartiles.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/1027'>Full article</a></strong>
                                        ")

## Review

Jump to: Research

24 pages, 2306 KiB   [ __](/2072-6643/14/3/529/pdf?version=1643189531 "Article PDF")

Open AccessReview

[Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review](/2072-6643/14/3/529)

by **Robert Percy Marshall** , **Jan-Niklas Droste** , **Jürgen Giessing** and **Richard B. Kreider**

_Nutrients_ **2022** , _14_(3), 529; <https://doi.org/10.3390/nu14030529> \- 26 Jan 2022 

[Cited by 18](/2072-6643/14/3/529#metrics) | Viewed by 17615 

**Abstract**

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some  [...] Read more.

Creatine monohydrate (CrM) is one of the most widely used nutritional supplements among active individuals and athletes to improve high-intensity exercise performance and training adaptations. However, research suggests that CrM supplementation may also serve as a therapeutic tool in the management of some chronic and traumatic diseases. Creatine supplementation has been reported to improve high-energy phosphate availability as well as have antioxidative, neuroprotective, anti-lactatic, and calcium-homoeostatic effects. These characteristics may have a direct impact on mitochondrion's survival and health particularly during stressful conditions such as ischemia and injury. This narrative review discusses current scientific evidence for use or supplemental CrM as a therapeutic agent during conditions associated with mitochondrial dysfunction. Based on this analysis, it appears that CrM supplementation may have a role in improving cellular bioenergetics in several mitochondrial dysfunction-related diseases, ischemic conditions, and injury pathology and thereby could provide therapeutic benefit in the management of these conditions. However, larger clinical trials are needed to explore these potential therapeutic applications before definitive conclusions can be drawn. [Full article](/2072-6643/14/3/529)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-14-00529/article_deploy/html/images/nutrients-14-00529-g001-550.jpg?1643189620 "
                    <strong>Figure 1</strong><br/>
                                            <p>General overview of the metabolic role of creatine in the creatine kinase/phosphocreatine \(CK/PCr\) system \[<a href="#B1-nutrients-14-00529" class="html-bibr">1</a>\]. The diagram depicts connected subcellular energy production and cellular mechanics of creatine metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum \(mitochondrial interactosome and oxidative metabolism\), phosphagen and glycolytic system \(extramitochondrial ATP production\), the linker of nucleoskeleton and cytoskeleton complex \(nesprins interaction with microtubules, actin polymerization, β-tubulins\), motor proteins \(e.g., myofibrillar ATPase machinery, vesicles transport\), and ion pumps \(e.g., SERCA, Na<sup>+</sup>/K<sup>+</sup>-ATPase\). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality. Several proteins of the endoplasmic reticulum–mitochondria organizing network \(ERMIONE\), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na<sup>+</sup>/Cl<sup>−</sup>-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca<sup>2+</sup> ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Reprinted with permission. See Bonilla et al. \[<a href="#B1-nutrients-14-00529" class="html-bibr">1</a>\] for more details about the metabolic basis of creatine in energy production and disease.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/529'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00529/article_deploy/html/images/nutrients-14-00529-g002-550.jpg?1643189620 "
                    <strong>Figure 2</strong><br/>
                                            <p>Panel <b>A</b>: Intracellular cascade after injury, infarction or contusion leads to mitochondrial dysfunction. Panel <b>B</b>: Impact of creatine on mitochondrial dysfunction. Green shows direct increase/stimulation of Cr/PCr, red shows direct decrease/inhibition of Cr/PCr, dotted line represents indirect impact of Cr/PCr on cellular pathways. ATP is adenosine triphosphate; Cr is creatine; PCr is phosphocreatine; ROS is reactive oxygen species; mPTP is mitochondrial permeability transition pore. Adapted from Dean et al. \[<a href="#B55-nutrients-14-00529" class="html-bibr">55</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/529'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00529/article_deploy/html/images/nutrients-14-00529-g003-550.jpg?1643189620 "
                    <strong>Figure 3</strong><br/>
                                            <p>Warburg Effect: glycolysis produces 2 ATP instead of 36 ATP, in pathological tissues even despite aerobic conditions. Glc is glucose, Oxy is oxygen, ATP is adenosine triphosphate. Adapted from Vander Heiden et al. \[<a href="#B91-nutrients-14-00529" class="html-bibr">91</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/529'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00529/article_deploy/html/images/nutrients-14-00529-g004-550.jpg?1643189620 "
                    <strong>Figure 4</strong><br/>
                                            <p>Mitochondrial dysfunction and non-communicable diseases. Adapted from Diaz-Vegas et al. \[<a href="#B90-nutrients-14-00529" class="html-bibr">90</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/3/529'>Full article</a></strong>
                                        ")

9 pages, 1049 KiB   [ __](/2072-6643/14/1/75/pdf?version=1640659936 "Article PDF")

Open AccessFeature PaperReview

[Safety of Dietary Guanidinoacetic Acid: A Villain of a Good Guy?](/2072-6643/14/1/75)

by **Sergej M. Ostojic**

_Nutrients_ **2022** , _14_(1), 75; <https://doi.org/10.3390/nu14010075> \- 24 Dec 2021 

[Cited by 18](/2072-6643/14/1/75#metrics) | Viewed by 5309 

**Abstract**

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary  [...] Read more.

Guanidinoacetic acid (GAA) is a natural amino acid derivative that is well-recognized for its central role in the biosynthesis of creatine, an essential compound involved in cellular energy metabolism. GAA (also known as glycocyamine or betacyamine) has been investigated as an energy-boosting dietary supplement in humans for more than 70 years. GAA is suggested to effectively increase low levels of tissue creatine and improve clinical features of cardiometabolic and neurological diseases, with GAA often outcompeting traditional bioenergetics agents in maintaining ATP status during stress. This perhaps happens due to a favorable delivery of GAA through specific membrane transporters (such as SLC6A6 and SLC6A13), previously dismissed as un-targetable carriers by other therapeutics, including creatine. The promising effects of dietary GAA might be countered by side-effects and possible toxicity. Animal studies reported neurotoxic and pro-oxidant effects of GAA accumulation, with exogenous GAA also appearing to increase methylation demand and circulating homocysteine, implying a possible metabolic burden of GAA intervention. This mini-review summarizes GAA toxicity evidence in human nutrition and outlines functional GAA safety through benefit-risk assessment and multi-criteria decision analysis. [Full article](/2072-6643/14/1/75)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-14-00075/article_deploy/html/images/nutrients-14-00075-g001-550.jpg?1640682052 "
                    <strong>Figure 1</strong><br/>
                                            <p>Metabolism and transport channels of guanidinoacetic acid \(GAA\). Abbreviations: AGAT, L-arginine:glycine amidinotransferase; SAM, <span class="html-italic">S</span>-adenosyl-L-methionine; GAMT, guanidinoacetate N-methyltransferase; SAH, <span class="html-italic">S</span>-adenosyl-L-homocysteine; CK, creatine kinase; PCR, phosphocreatine; AHCY, adenosylhomocysteinase; ATP, adenosine triphosphate; ADP, adenosine diphosphate. Yellow shapes depict different influx and efflux cellular transporters for GAA, including creatine transporter \(SLC6A8\), GABA transporter \(SLC6A13\), taurine transporter \(SLC6A6\), and 5-monocarboxylate transporter 12 \(SLC16A12\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/1/75'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-14-00075/article_deploy/html/images/nutrients-14-00075-g002-550.jpg?1640682052 "
                    <strong>Figure 2</strong><br/>
                                            <p>Risk-benefit tree and performance matrix for a hypothetical guanidinoacetic acid \(GAA\) case study.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/14/1/75'>Full article</a></strong>
                                        ")

14 pages, 885 KiB   [ __](/2072-6643/13/8/2844/pdf?version=1629343350 "Article PDF")

Open AccessReview

[Timing of Creatine Supplementation around Exercise: A Real Concern?](/2072-6643/13/8/2844)

by **Felipe Ribeiro** , **Igor Longobardi** , **Pedro Perim** , **Breno Duarte** , **Pedro Ferreira** , **Bruno Gualano** , **Hamilton Roschel** and **Bryan Saunders**

_Nutrients_ **2021** , _13_(8), 2844; <https://doi.org/10.3390/nu13082844> \- 19 Aug 2021 

[Cited by 14](/2072-6643/13/8/2844#metrics) | Viewed by 33258 

**Abstract**

Creatine has been considered an effective ergogenic aid for several decades; it can help athletes engaged in a variety of sports and obtain performance gains. Creatine supplementation increases muscle creatine stores; several factors have been identified that may modify the intramuscular increase and  [...] Read more.

Creatine has been considered an effective ergogenic aid for several decades; it can help athletes engaged in a variety of sports and obtain performance gains. Creatine supplementation increases muscle creatine stores; several factors have been identified that may modify the intramuscular increase and subsequent performance benefits, including baseline muscle Cr content, type II muscle fibre content and size, habitual dietary intake of Cr, aging, and exercise. Timing of creatine supplementation in relation to exercise has recently been proposed as an important consideration to optimise muscle loading and performance gains, although current consensus is lacking regarding the ideal ingestion time. Research has shifted towards comparing creatine supplementation strategies pre-, during-, or post-exercise. Emerging evidence suggests greater benefits when creatine is consumed after exercise compared to pre-exercise, although methodological limitations currently preclude solid conclusions. Furthermore, physiological and mechanistic data are lacking, in regard to claims that the timing of creatine supplementation around exercise moderates gains in muscle creatine and exercise performance. This review discusses novel scientific evidence on the timing of creatine intake, the possible mechanisms that may be involved, and whether the timing of creatine supplementation around exercise is truly a real concern. [Full article](/2072-6643/13/8/2844)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-02844/article_deploy/html/images/nutrients-13-02844-g001-550.jpg?1629343447 "
                    <strong>Figure 1</strong><br/>
                                            <p>The hypothetical mechanisms behind an exercise-mediated increase in total creatine content with creatine supplementation. \(<b>Panel A</b>\): exercise hyperaemia increases tissue perfusion, enhancing creatine delivery. Additionally, increased Na+/K+ pump activity during exercise supports the \[Na<sup>+</sup>\] gradient favouring creatine uptake by CreaT. Together, these effects may acutely potentiate the uptake and increase in total muscle creatine content. \(<b>Panel B</b>\): theoretical overlap of events according to the timing of creatine supplementation, in relation to exercise and its potential benefits regarding the delivery and uptake of creatine to the muscle. Created with BioRender.com.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2844'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02844/article_deploy/html/images/nutrients-13-02844-g002-550.jpg?1629343447 "
                    <strong>Figure 2</strong><br/>
                                            <p>Overview of what is known about the timing of creatine \(Cr\) supplementation and what is yet to be determined. TCr = total creatine. Created with BioRender.com.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2844'>Full article</a></strong>
                                        ")

14 pages, 768 KiB   [ __](/2072-6643/13/8/2709/pdf?version=1628239720 "Article PDF")

Open AccessReview

[Chronic Dialysis Patients Are Depleted of Creatine: Review and Rationale for Intradialytic Creatine Supplementation](/2072-6643/13/8/2709)

by **Yvonne van der Veen** , **Adrian Post** , **Daan Kremer** , **Christa A. Koops** , **Erik Marsman** , **Theo Y. Jerôme Appeldoorn** , **Daan J. Touw** , **Ralf Westerhuis** , **Margaretha Rebecca Heiner-Fokkema** , **Casper F. M. Franssen** , **Theo Wallimann** and **Stephan J. L. Bakker**

_Nutrients_ **2021** , _13_(8), 2709; <https://doi.org/10.3390/nu13082709> \- 6 Aug 2021 

[Cited by 7](/2072-6643/13/8/2709#metrics) | Viewed by 6475 

**Abstract**

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis,  [...] Read more.

There is great need for the identification of new, potentially modifiable risk factors for the poor health-related quality of life (HRQoL) and of the excess risk of mortality in dialysis-dependent chronic kidney disease patients. Creatine is an essential contributor to cellular energy homeostasis, yet, on a daily basis, 1.6–1.7% of the total creatine pool is non-enzymatically degraded to creatinine and subsequently lost via urinary excretion, thereby necessitating a continuous supply of new creatine in order to remain in steady-state. Because of an insufficient ability to synthesize creatine, unopposed losses to the dialysis fluid, and insufficient intake due to dietary recommendations that are increasingly steered towards more plant-based diets, hemodialysis patients are prone to creatine deficiency, and may benefit from creatine supplementation. To avoid problems with compliance and fluid balance, and, furthermore, to prevent intradialytic losses of creatine to the dialysate, we aim to investigate the potential of intradialytic creatine supplementation in improving outcomes. Given the known physiological effects of creatine, intradialytic creatine supplementation may help to maintain creatine homeostasis among dialysis-dependent chronic kidney disease patients, and consequently improve muscle status, nutritional status, neurocognitive status, HRQoL. Additionally, we describe the rationale and design for a block-randomized, double-blind, placebo-controlled pilot study. The aim of the pilot study is to explore the creatine uptake in the circulation and tissues following different creatine supplementation dosages. [Full article](/2072-6643/13/8/2709)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-02709/article_deploy/html/images/nutrients-13-02709-g001-550.jpg?1628239806 "
                    <strong>Figure 1</strong><br/>
                                            <p>Simplified schematic overview of creatine homeostasis. AGAT-arginine:glycine amidino-transferase; GAMT-guanidinoacetate methyltransferase.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2709'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-02709/article_deploy/html/images/nutrients-13-02709-g002-550.jpg?1628239806 "
                    <strong>Figure 2</strong><br/>
                                            <p>Timeline overview.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/8/2709'>Full article</a></strong>
                                        ")

42 pages, 1253 KiB   [ __](/2072-6643/13/6/1915/pdf?version=1622727992 "Article PDF")

Open AccessReview

[Creatine for Exercise and Sports Performance, with Recovery Considerations for Healthy Populations](/2072-6643/13/6/1915)

by **Benjamin Wax** , **Chad M. Kerksick** , **Andrew R. Jagim** , **Jerry J. Mayo** , **Brian C. Lyons** and **Richard B. Kreider**

_Nutrients_ **2021** , _13_(6), 1915; <https://doi.org/10.3390/nu13061915> \- 2 Jun 2021 

[Cited by 62](/2072-6643/13/6/1915#metrics) | Viewed by 75697 

**Abstract**

Creatine is one of the most studied and popular ergogenic aids for athletes and recreational weightlifters seeking to improve sport and exercise performance, augment exercise training adaptations, and mitigate recovery time. Studies consistently reveal that creatine supplementation exerts positive ergogenic effects on single  [...] Read more.

Creatine is one of the most studied and popular ergogenic aids for athletes and recreational weightlifters seeking to improve sport and exercise performance, augment exercise training adaptations, and mitigate recovery time. Studies consistently reveal that creatine supplementation exerts positive ergogenic effects on single and multiple bouts of short-duration, high-intensity exercise activities, in addition to potentiating exercise training adaptations. In this respect, supplementation consistently demonstrates the ability to enlarge the pool of intracellular creatine, leading to an amplification of the cell’s ability to resynthesize adenosine triphosphate. This intracellular expansion is associated with several performance outcomes, including increases in maximal strength (low-speed strength), maximal work output, power production (high-speed strength), sprint performance, and fat-free mass. Additionally, creatine supplementation may speed up recovery time between bouts of intense exercise by mitigating muscle damage and promoting the faster recovery of lost force-production potential. Conversely, contradictory findings exist in the literature regarding the potential ergogenic benefits of creatine during intermittent and continuous endurance-type exercise, as well as in those athletic tasks where an increase in body mass may hinder enhanced performance. The purpose of this review was to summarize the existing literature surrounding the efficacy of creatine supplementation on exercise and sports performance, along with recovery factors in healthy populations. [Full article](/2072-6643/13/6/1915)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01915/article_deploy/html/images/nutrients-13-01915-g001-550.jpg?1622728070 "
                    <strong>Figure 1</strong><br/>
                                            <p>General flow diagram highlighting the selection process for included articles.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1915'>Full article</a></strong>
                                        ")

_attachment_

Supplementary material:   
[ Supplementary File 1 (ZIP, 119 KiB) ](/2072-6643/13/6/1912/s1?version=1622624142)  


14 pages, 1376 KiB   [ __](/2072-6643/13/6/1912/pdf?version=1622624141 "Article PDF")

Open AccessReview

[Meta-Analysis Examining the Importance of Creatine Ingestion Strategies on Lean Tissue Mass and Strength in Older Adults](/2072-6643/13/6/1912)

by **Scott C. Forbes** , **Darren G. Candow** , **Sergej M. Ostojic** , **Michael D. Roberts** and **Philip D. Chilibeck**

_Nutrients_ **2021** , _13_(6), 1912; <https://doi.org/10.3390/nu13061912> \- 2 Jun 2021 

[Cited by 45](/2072-6643/13/6/1912#metrics) | Viewed by 31480 

**Abstract**

Creatine supplementation in conjunction with resistance training (RT) augments gains in lean tissue mass and strength in aging adults; however, there is a large amount of heterogeneity between individual studies that may be related to creatine ingestion strategies. Therefore, the purpose of this  [...] Read more.

Creatine supplementation in conjunction with resistance training (RT) augments gains in lean tissue mass and strength in aging adults; however, there is a large amount of heterogeneity between individual studies that may be related to creatine ingestion strategies. Therefore, the purpose of this review was to (1) perform updated meta-analyses comparing creatine vs. placebo (independent of dosage and frequency of ingestion) during a resistance training program on measures of lean tissue mass and strength, (2) perform meta-analyses examining the effects of different creatine dosing strategies (lower: ≤5 g/day and higher: >5 g/day), with and without a creatine-loading phase (≥20 g/day for 5–7 days), and (3) perform meta-analyses determining whether creatine supplementation only on resistance training days influences measures of lean tissue mass and strength. Overall, creatine (independent of dosing strategy) augments lean tissue mass and strength increase from RT vs. placebo. Subanalyses showed that creatine-loading followed by lower-dose creatine (≤5 g/day) increased chest press strength vs. placebo. Higher-dose creatine (>5 g/day), with and without a creatine-loading phase, produced significant gains in leg press strength vs. placebo. However, when studies involving a creatine-loading phase were excluded from the analyses, creatine had no greater effect on chest press or leg press strength vs. placebo. Finally, creatine supplementation only on resistance training days significantly increased measures of lean tissue mass and strength vs. placebo. [Full article](/2072-6643/13/6/1912)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g001-550.jpg?1622624230 "
                    <strong>Figure 1</strong><br/>
                                            <p>Forest plot of studies on lean tissue mass with sub-analyses using lower-dose creatine studies \(≤5 g/day\) and of higher-dose creatine studies \(&gt;5 g/day\) on lean tissue mass.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g002-550.jpg?1622624230 "
                    <strong>Figure 2</strong><br/>
                                            <p>Forest plot of studies on chest press strength.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g003-550.jpg?1622624230 "
                    <strong>Figure 3</strong><br/>
                                            <p>Forest plot of lower-dose creatine studies \(≤5 g/day\) on chest press strength with exclusion of creatine loading studies.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g004-550.jpg?1622624230 "
                    <strong>Figure 4</strong><br/>
                                            <p>Forest plot of studies on leg press strength.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g005-550.jpg?1622624230 "
                    <strong>Figure 5</strong><br/>
                                            <p>Forest plot of higher-dose creatine studies \(&gt;5 g/day\) on leg press strength with exclusion of creatine-loading studies.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g006-550.jpg?1622624230 "
                    <strong>Figure 6</strong><br/>
                                            <p>Forest plot of studies on lean tissue mass.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g007-550.jpg?1622624230 "
                    <strong>Figure 7</strong><br/>
                                            <p>Forest plot of studies on chest press strength.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01912/article_deploy/html/images/nutrients-13-01912-g008-550.jpg?1622624230 "
                    <strong>Figure 8</strong><br/>
                                            <p>Forest plot of studies on leg press strength.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1912'>Full article</a></strong>
                                        ")

24 pages, 5954 KiB   [ __](/2072-6643/13/6/1825/pdf?version=1622104400 "Article PDF")

Open AccessReview

[The Application of Creatine Supplementation in Medical Rehabilitation](/2072-6643/13/6/1825)

by **Kylie K. Harmon** , **Jeffrey R. Stout** , **David H. Fukuda** , **Patrick S. Pabian** , **Eric S. Rawson** and **Matt S. Stock**

_Nutrients_ **2021** , _13_(6), 1825; <https://doi.org/10.3390/nu13061825> \- 27 May 2021 

[Cited by 24](/2072-6643/13/6/1825#metrics) | Viewed by 23456 

**Abstract**

Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle  [...] Read more.

Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine’s potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation. [Full article](/2072-6643/13/6/1825)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01825/article_deploy/html/images/nutrients-13-01825-g001-550.jpg?1622104467 "
                    <strong>Figure 1</strong><br/>
                                            <p>Rationale for examination of creatine supplementation as a rehabilitative aid. Abbreviations defined from clockwise: COPD = chronic obstructive pulmonary disease; ALS = amyotrophic lateral sclerosis.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/6/1825'>Full article</a></strong>
                                        ")

13 pages, 710 KiB   [ __](/2072-6643/13/5/1633/pdf?version=1620895868 "Article PDF")

Open AccessReview

[Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy](/2072-6643/13/5/1633)

by **Bo Li** and **Lili Yang**

_Nutrients_ **2021** , _13_(5), 1633; <https://doi.org/10.3390/nu13051633> \- 13 May 2021 

[Cited by 19](/2072-6643/13/5/1633#metrics) | Viewed by 7391 

**Abstract**

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine  [...] Read more.

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed. [Full article](/2072-6643/13/5/1633)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01633/article_deploy/html/images/nutrients-13-01633-g001-550.jpg?1620895938 "
                    <strong>Figure 1</strong><br/>
                                            <p>The “hybrid-engine” model in T cell antitumor immunity and potential application of creatine supplementation for cancer immunotherapy. \(<b>A</b>\) Limited nutrients for immune cells in the tumor microenvironment. \(<b>B</b>\) The “hybrid-engine” model. Analogous to the hybrid car, a tumor antigen-specific CD8 T cell uses a “molecular fuel engine”, including tricarboxylic acid cycle and glycolysis, to convert nutrients into adenosine triphosphate \(ATP\), while utilizing creatine-mediated energy buffering system, a “molecular battery”, to store ATP and power T cell activities. \(<b>C</b>\) Creatine can be obtained from creatine-rich diet \(e.g., red meat, poultry, and fish\) and dietary supplements. \(<b>D</b>\) Creatine administration as a therapeutic intervention would result in the best therapeutic effects. ©2019 Di Biase et al. Originally published in <span class="html-italic">J. Exp. Med.</span> doi: 10.1084/jem.20182044.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/5/1633'>Full article</a></strong>
                                        ")

14 pages, 553 KiB   [ __](/2072-6643/13/5/1429/pdf?version=1623725445 "Article PDF")

Open AccessReview

[Creatine Supplementation for Patients with Inflammatory Bowel Diseases: A Scientific Rationale for a Clinical Trial](/2072-6643/13/5/1429)

by **Theo Wallimann** , **Caroline H. T. Hall** , **Sean P. Colgan** and **Louise E. Glover**

_Nutrients_ **2021** , _13_(5), 1429; <https://doi.org/10.3390/nu13051429> \- 23 Apr 2021 

[Cited by 22](/2072-6643/13/5/1429#metrics) | Viewed by 11478 

**Abstract**

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that "oral supplementation with creatine monohydrate (Cr), a pleiotropic  [...] Read more.

Based on theoretical considerations, experimental data with cells in vitro, animal studies in vivo, as well as a single case pilot study with one colitis patient, a consolidated hypothesis can be put forward, stating that “oral supplementation with creatine monohydrate (Cr), a pleiotropic cellular energy precursor, is likely to be effective in inducing a favorable response and/or remission in patients with inflammatory bowel diseases (IBD), like ulcerative colitis and/or Crohn’s disease”. A current pilot clinical trial that incorporates the use of oral Cr at a dose of 2 × 7 g per day, over an initial period of 2 months in conjunction with ongoing therapies (NCT02463305) will be informative for the proposed larger, more long-term Cr supplementation study of 2 × 3–5 g of Cr per day for a time of 3–6 months. This strategy should be insightful to the potential for Cr in reducing or alleviating the symptoms of IBD. Supplementation with chemically pure Cr, a natural nutritional supplement, is well tolerated not only by healthy subjects, but also by patients with diverse neuromuscular diseases. If the outcome of such a clinical pilot study with Cr as monotherapy or in conjunction with metformin were positive, oral Cr supplementation could then be used in the future as potentially useful adjuvant therapeutic intervention for patients with IBD, preferably together with standard medication used for treating patients with chronic ulcerative colitis and/or Crohn’s disease. [Full article](/2072-6643/13/5/1429)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01429/article_deploy/html/images/nutrients-13-01429-g001-550.jpg?1623725517 "
                    <strong>Figure 1</strong><br/>
                                            <p>Cr/CK shuttle and the intestinal mucosal barrier. Cr is derived from dietary sources in the gastrointestinal tract, or by de novo synthesis primarily in the kidney and in the liver \[<a href="#B12-nutrients-13-01429" class="html-bibr">12</a>\]. The Na<sup>+</sup> and Cl<sup>−</sup> dependent creatine transporter \(CrT1\), expressed in the apical membrane of intestinal epithelial cells, facilitates Cr uptake from the gut lumen \[<a href="#B11-nutrients-13-01429" class="html-bibr">11</a>,<a href="#B14-nutrients-13-01429" class="html-bibr">14</a>\]. Potential routes for Cr absorption into systemic circulation include paracellular movement by solvent drag transport, or via basolateral Cr transport by the monocarboxylate transporter 12 \(MCT12\) \[<a href="#B15-nutrients-13-01429" class="html-bibr">15</a>\]. Gut microbiota express specific enzymes that can mediate Cr and creatinine \(Crn\) breakdown. In hypoxic intestinal epithelial cells, cytosolic CK localizes to apical adherens junctions in complex with the actomyosin cytoskeletal network, providing a conduit for rapid ATP generation during the energy-dependent processes of epithelial junction assembly and barrier restitution \[<a href="#B16-nutrients-13-01429" class="html-bibr">16</a>\]. Adapted from \[<a href="#B17-nutrients-13-01429" class="html-bibr">17</a>\].</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/5/1429'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01429/article_deploy/html/images/nutrients-13-01429-g002-550.jpg?1623725517 "
                    <strong>Figure 2</strong><br/>
                                            <p>The PCr/Cr shuttle promotes mucosal barrier and wound healing by improving cellular energetics and by stabilization of the adherence junctions. During active inflammation, such as that seen in IBD, low O<sub>2</sub> levels result in the stabilization of HIF and resultant induction of creatine kinase \(CK\) isoenzymes and the Cr transporter \(CrT1\) within intestinal epithelial cells \(see \[<a href="#B16-nutrients-13-01429" class="html-bibr">16</a>,<a href="#B62-nutrients-13-01429" class="html-bibr">62</a>,<a href="#B63-nutrients-13-01429" class="html-bibr">63</a>\] for further details\). CK localizes to epithelial junctions that are stabilized by interactions with the actin cytoskeleton. In response to epithelial disruption during inflammation, large amounts of ATP are necessary to accommodate the demand for cytoskeletal reorganization, including the acto-myosin ATPase at epithelial cellular junctions. Under such conditions, CK and CrT1 coordinately promote wound healing and barrier function by generating ATP from PCr to efficiently promote homeostasis.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/5/1429'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01429/article_deploy/html/images/nutrients-13-01429-g003-550.jpg?1623725517 "
                    <strong>Figure 3</strong><br/>
                                            <p>Decreased expression of CrT1 in IBD promotes barrier dysfunction. Normal expression of CrT1 on the apical surface of intestinal epithelia \(left panel\) results in adequate supplies of Cr via dietary sources to promote healthy barrier function and intestinal homeostasis. Patients with IBD express lower levels of CrT1 \(right panel\) and disrupt the Cr-PCr energy shuttle to the extent that wound healing potential and barrier are dysfunctional \(see \[<a href="#B14-nutrients-13-01429" class="html-bibr">14</a>,<a href="#B16-nutrients-13-01429" class="html-bibr">16</a>\] for further details\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/5/1429'>Full article</a></strong>
                                        ")

32 pages, 3304 KiB   [ __](/2072-6643/13/4/1238/pdf?version=1678334027 "Article PDF")

Open AccessReview

[Metabolic Basis of Creatine in Health and Disease: A Bioinformatics-Assisted Review](/2072-6643/13/4/1238)

by **Diego A. Bonilla** , **Richard B. Kreider** , **Jeffrey R. Stout** , **Diego A. Forero** , **Chad M. Kerksick** , **Michael D. Roberts** and **Eric S. Rawson**

_Nutrients_ **2021** , _13_(4), 1238; <https://doi.org/10.3390/nu13041238> \- 9 Apr 2021 

[Cited by 85](/2072-6643/13/4/1238#metrics) | Viewed by 20655 

**Abstract**

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl−-dependent Cr  [...] Read more.

Creatine (Cr) is a ubiquitous molecule that is synthesized mainly in the liver, kidneys, and pancreas. Most of the Cr pool is found in tissues with high-energy demands. Cr enters target cells through a specific symporter called Na+/Cl−-dependent Cr transporter (CRT). Once within cells, creatine kinase (CK) catalyzes the reversible transphosphorylation reaction between [Mg2+:ATP4−]2− and Cr to produce phosphocreatine (PCr) and [Mg2+:ADP3−]−. We aimed to perform a comprehensive and bioinformatics-assisted review of the most recent research findings regarding Cr metabolism. Specifically, several public databases, repositories, and bioinformatics tools were utilized for this endeavor. Topics of biological complexity ranging from structural biology to cellular dynamics were addressed herein. In this sense, we sought to address certain pre-specified questions including: (i) What happens when creatine is transported into cells? (ii) How is the CK/PCr system involved in cellular bioenergetics? (iii) How is the CK/PCr system compartmentalized throughout the cell? (iv) What is the role of creatine amongst different tissues? and (v) What is the basis of creatine transport? Under the cellular allostasis paradigm, the CK/PCr system is physiologically essential for life (cell survival, growth, proliferation, differentiation, and migration/motility) by providing an evolutionary advantage for rapid, local, and temporal support of energy- and mechanical-dependent processes. Thus, we suggest the CK/PCr system acts as a dynamic biosensor based on chemo-mechanical energy transduction, which might explain why dysregulation in Cr metabolism contributes to a wide range of diseases besides the mitigating effect that Cr supplementation may have in some of these disease states. [Full article](/2072-6643/13/4/1238)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01238/article_deploy/html/images/nutrients-13-01238-ag-550.jpg?1678334108 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1238'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01238/article_deploy/html/images/nutrients-13-01238-g001-550.jpg?1678334096 "
                    <strong>Figure 1</strong><br/>
                                            <p>Creatine synthesis/excretion and the creatine kinase reaction. Enzymes are represented by ovals. Once synthesized from L-arginine, glycine, and S-adenosyl-L-methionine, creatine \(Cr\) is converted to phosphocreatine \(PCr\) by means of the creatine kinase \(CK\), which catalyzes the reversible transference of a phosphoryl group \(PO<sub>3</sub><sup>2−</sup>\), not a phosphate \(PO<sub>4</sub><sup>3−</sup>\), from ATP. The kinetic rate of the non-enzymatic conversion of Cr \(or PCr\) to creatinine \(Crn\) depends on the H<sup>+</sup> concentration of the media. It is important to note that neither Crn nor PCr are substrates of the sodium- and chloride-dependent creatine transporter \(not shown\). Oval size represents the expression level of AGAT \(black\), GAMT \(white\), and CK \(orange\) in some tissues. For more details related to expression in different tissues or conditions \(i.e., pathologies\) use the following BioGPS ID numbers: AGAT–2628; GAMT–2593. AGAT: L-Arginine-Glycine amidinotransferase; GAMT: Guanidinoacetate N-Methyltransferase; H<sup>+</sup>: hydrogen ion; Pi: inorganic phosphate. Modified with permission from Bonilla and Moreno \[<a href="#B7-nutrients-13-01238" class="html-bibr">7</a>\] using the Freeware ACD/ChemSketch 2021 \(Advanced Chemistry Development, Inc., Toronto, ON, Canada\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1238'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01238/article_deploy/html/images/nutrients-13-01238-g002-550.jpg?1678334096 "
                    <strong>Figure 2</strong><br/>
                                            <p>Clustering of CK-interacting proteins using the Markov Cluster Algorithm. Network nodes represent proteins while edges represent protein–protein associations. The red cluster includes a subgroup of enzymes participating in the tricarboxylic acid cycle that are represented in the graph with blue nodes. To visualize our interactive network access to this permanent link: <a href="https://version-11-0b.string-db.org/cgi/network?networkId=bu20zAE45PpB" target="_blank">https://version-11-0b.string-db.org/cgi/network?networkId=bu20zAE45PpB</a> \(accessed on 14 February 2021\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1238'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01238/article_deploy/html/images/nutrients-13-01238-g003-550.jpg?1678334099 "
                    <strong>Figure 3</strong><br/>
                                            <p>General overview of the CK/PCr system. The diagram represents the super-connected subcellular energy production and cellular mechanics of Cr metabolism. This chemo-mechanical energy transduction network involves structural and functional coupling of the mitochondrial reticulum \(mitochondrial interactosome and oxidative metabolism\), phosphagen and glycolytic system \(extramitochondrial ATP production\), the linker of nucleoskeleton and cytoskeleton complex \(nesprins interaction with microtubules, actin polymerization, β-tubulins\), motor proteins \(e.g., myofibrillar ATPase machinery, vesicles transport\), and ion pumps \(e.g., SERCA, Na<sup>+</sup>/K<sup>+</sup>-ATPase\). The cardiolipin-rich domain is represented by parallel black lines. Green sparkled circles represent the subcellular processes where the CK/PCr system is important for functionality \(see the previous sections for rationale and citations\). Several proteins of the endoplasmic reticulum–mitochondria organizing network \(ERMIONE\), the SERCA complex, the TIM/TOM complex, the MICOS complex, the linker of nucleoskeleton and cytoskeleton complex, and the architecture of sarcomere and cytoskeleton are not depicted for readability. ANT: adenine nucleotide translocase; CK: creatine kinase; Cr: creatine; Crn: creatinine; CRT: Na<sup>+</sup>/Cl<sup>−</sup>-dependent creatine transporter; ERMES: endoplasmic reticulum-mitochondria encounter structure; ETC: electron transport chain; GLUT-4: glucose transporter type 4; HK: hexokinase; mdm10: mitochondrial distribution and morphology protein 10; MICOS: mitochondrial contact site and cristae organizing system; NDPK: nucleoside-diphosphate kinase; NPC: nuclear pore complex; PCr: phosphocreatine; SAM: sorting and assembly machinery; SERCA: Sarco/Endoplasmic Reticulum Ca<sup>2+</sup> ATPase; TIM: translocase of the inner membrane complex; TOM: translocase of the outer membrane complex; UCP: uncoupling protein; VDAC: voltage-dependent anion channel. Source: designed by the authors \(D.A.B.\) using figure templates developed by Servier Medical Art \(Les Laboratoires Servier, Suresnes, France\), licensed under a Creative Common Attribution 3.0 Generic License. <a href="http://smart.servier.com/" target="_blank">http://smart.servier.com/</a> \(accessed on 14 January 2021\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1238'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-01238/article_deploy/html/images/nutrients-13-01238-g004-550.jpg?1678334097 "
                    <strong>Figure 4</strong><br/>
                                            <p>Importance of Cr metabolism in whole-body physiology. The CK/PCr system is essential for the chemo-mechanical energy transduction of cells/tissues with high, fluctuant, and constant energy demands. Source: designed by the authors \(D.A.B.\) using an anatomy template developed by 3dMediSphere \(<a href="https://www.turbosquid.com/" target="_blank">https://www.turbosquid.com/</a>\), licensed 3D standard Vray 3.60. accessed on 14 February 2020.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1238'>Full article</a></strong>
                                        ")

18 pages, 704 KiB   [ __](/2072-6643/13/4/1215/pdf?version=1617941072 "Article PDF")

Open AccessReview

[Role of Creatine in the Heart: Health and Disease](/2072-6643/13/4/1215)

by **Maurizio Balestrino**

_Nutrients_ **2021** , _13_(4), 1215; <https://doi.org/10.3390/nu13041215> \- 7 Apr 2021 

[Cited by 44](/2072-6643/13/4/1215#metrics) | Viewed by 17889 

**Abstract**

Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation (throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine) increases creatine content even in  [...] Read more.

Creatine is a key player in heart contraction and energy metabolism. Creatine supplementation (throughout the paper, only supplementation with creatine monohydrate will be reviewed, as this is by far the most used and best-known way of supplementing creatine) increases creatine content even in the normal heart, and it is generally safe. In heart failure, creatine and phosphocreatine decrease because of decreased expression of the creatine transporter, and because phosphocreatine degrades to prevent adenosine triphosphate (ATP) exhaustion. This causes decreased contractility reserve of the myocardium and correlates with left ventricular ejection fraction, and it is a predictor of mortality. Thus, there is a strong rationale to supplement with creatine the failing heart. Pending additional trials, creatine supplementation in heart failure may be useful given data showing its effectiveness (1) against specific parameters of heart failure, and (2) against the decrease in muscle strength and endurance of heart failure patients. In heart ischemia, the majority of trials used phosphocreatine, whose mechanism of action is mostly unrelated to changes in the ergogenic creatine-phosphocreatine system. Nevertheless, preliminary data with creatine supplementation are encouraging, and warrant additional studies. Prevention of cardiac toxicity of the chemotherapy compounds anthracyclines is a novel field where creatine supplementation may also be useful. Creatine effectiveness in this case may be because anthracyclines reduce expression of the creatine transporter, and because of the pleiotropic antioxidant properties of creatine. Moreover, creatine may also reduce concomitant muscle damage by anthracyclines. [Full article](/2072-6643/13/4/1215)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-01215/article_deploy/html/images/nutrients-13-01215-g001-550.jpg?1628073764 "
                    <strong>Figure 1</strong><br/>
                                            <p>The primary sources for blood-borne creatine \(Cr\) are diet \(meat\) and a two-step biosynthesis that occurs primarily in the kidney, liver, and pancreas. Cr, a β-amino acid, is made by the transfer of glycine onto the arginine side chain catalyzed by arginine:glycine amidinotransferase \(AGAT\) to form guanidinoacetate. The methyl group is transferred to the guanidino group via guanidinoacetate methyltransferase \(GAMT\). Cr accumulates in muscles and brain through the action of the Cr transporter \(CrT\) in the sarcolemma. Cr is trapped by phosphorylation to phosphocreatine \(PCr, see structure\) by creatine kinase \(CK\). ADP—adenosine diphosphate; ATP—adenosine triphosphate; CrP—creatine phosphate. Reprinted by permission from Springer Nature Customer Service Centre GmbH:Springer Nature, Current Hypertension Reports \(On the hypothesis that the failing heart is energy starved: Lessons learned from the metabolism of ATP and creatine, Joanne S. Ingwall\) Copyright Springer Nature Customer Service Centre GmbH, 2006.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/4/1215'>Full article</a></strong>
                                        ")

17 pages, 1219 KiB   [ __](/2072-6643/13/3/877/pdf?version=1615545561 "Article PDF")

Open AccessReview

[Creatine Supplementation in Women’s Health: A Lifespan Perspective](/2072-6643/13/3/877)

by **Abbie E Smith-Ryan** , **Hannah E Cabre** , **Joan M Eckerson** and **Darren G Candow**

_Nutrients_ **2021** , _13_(3), 877; <https://doi.org/10.3390/nu13030877> \- 8 Mar 2021 

[Cited by 37](/2072-6643/13/3/877#metrics) | Viewed by 61731 

**Abstract**

Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70-80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for  [...] Read more.

Despite extensive research on creatine, evidence for use among females is understudied. Creatine characteristics vary between males and females, with females exhibiting 70–80% lower endogenous creatine stores compared to males. Understanding creatine metabolism pre- and post-menopause yields important implications for creatine supplementation for performance and health among females. Due to the hormone-related changes to creatine kinetics and phosphocreatine resynthesis, supplementation may be particularly important during menses, pregnancy, post-partum, during and post-menopause. Creatine supplementation among pre-menopausal females appears to be effective for improving strength and exercise performance. Post-menopausal females may also experience benefits in skeletal muscle size and function when consuming high doses of creatine (0.3 g·kg−1·d−1); and favorable effects on bone when combined with resistance training. Pre-clinical and clinical evidence indicates positive effects from creatine supplementation on mood and cognition, possibly by restoring brain energy levels and homeostasis. Creatine supplementation may be even more effective for females by supporting a pro-energetic environment in the brain. The purpose of this review was to highlight the use of creatine in females across the lifespan with particular emphasis on performance, body composition, mood, and dosing strategies. [Full article](/2072-6643/13/3/877)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00877/article_deploy/html/images/nutrients-13-00877-g001-550.jpg?1615545672 "
                    <strong>Figure 1</strong><br/>
                                            <p>A theoretical model for the interplay between creatine kinase and menstrual cycle hormones \[<a href="#B6-nutrients-13-00877" class="html-bibr">6</a>,<a href="#B10-nutrients-13-00877" class="html-bibr">10</a>,<a href="#B11-nutrients-13-00877" class="html-bibr">11</a>\]. Creatine metabolism and creatine kinase concentrations vary throughout the menstrual cycle and lifecycle. These alterations may also influence metabolic characteristics of protein and carbohydrate oxidation \[<a href="#B12-nutrients-13-00877" class="html-bibr">12</a>\], which provides a physiological basis for the potential use of creatine supplementation for females.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/877'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00877/article_deploy/html/images/nutrients-13-00877-g002-550.jpg?1615545672 "
                    <strong>Figure 2</strong><br/>
                                            <p>The relative effects of creatine supplementation in comparison to placebo for strength performance in females.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/877'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00877/article_deploy/html/images/nutrients-13-00877-g003-550.jpg?1615545672 "
                    <strong>Figure 3</strong><br/>
                                            <p>The relative effects of creatine supplementation in comparison to a placebo on exercise performance in females.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/877'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00877/article_deploy/html/images/nutrients-13-00877-g004-550.jpg?1615545672 "
                    <strong>Figure 4</strong><br/>
                                            <p>The relative effects of creatine supplementation in comparison to placebo on sports performance in females.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/877'>Full article</a></strong>
                                        ")

28 pages, 894 KiB   [ __](/2072-6643/13/3/857/pdf?version=1614940249 "Article PDF")

Open AccessReview

[The Potential Role of Creatine in Vascular Health](/2072-6643/13/3/857)

by **Holly Clarke** , **Robert C. Hickner** and **Michael J. Ormsbee**

_Nutrients_ **2021** , _13_(3), 857; <https://doi.org/10.3390/nu13030857> \- 5 Mar 2021 

[Cited by 23](/2072-6643/13/3/857#metrics) | Viewed by 13681 

**Abstract**

Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to  [...] Read more.

Creatine is an organic compound, consumed exogenously in the diet and synthesized endogenously via an intricate inter-organ process. Functioning in conjunction with creatine kinase, creatine has long been known for its pivotal role in cellular energy provision and energy shuttling. In addition to the abundance of evidence supporting the ergogenic benefits of creatine supplementation, recent evidence suggests a far broader application for creatine within various myopathies, neurodegenerative diseases, and other pathologies. Furthermore, creatine has been found to exhibit non-energy related properties, contributing as a possible direct and in-direct antioxidant and eliciting anti-inflammatory effects. In spite of the new clinical success of supplemental creatine, there is little scientific insight into the potential effects of creatine on cardiovascular disease (CVD), the leading cause of mortality. Taking into consideration the non-energy related actions of creatine, highlighted in this review, it can be speculated that creatine supplementation may serve as an adjuvant therapy for the management of vascular health in at-risk populations. This review, therefore, not only aims to summarize the current literature surrounding creatine and vascular health, but to also shed light onto the potential mechanisms in which creatine may be able to serve as a beneficial supplement capable of imparting vascular-protective properties and promoting vascular health. [Full article](/2072-6643/13/3/857)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00857/article_deploy/html/images/nutrients-13-00857-ag-550.jpg?1614940322 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/857'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00857/article_deploy/html/images/nutrients-13-00857-g001-550.jpg?1614940322 "
                    <strong>Figure 1</strong><br/>
                                            <p>Novel mechanisms by which creatine supplementation may benefit vascular health and function; PCr = phosphocreatine, Cr = creatine, EC = endothelial cell, DNA = deoxyribonucleic acid, RNA = ribonucleic acid, ETC = mitochondria electron transport chain, mtROS = mitochondrial-specific reactive oxygen species, ROS = reactive oxygen species, LDL = low density lipoprotein, TC = total cholesterol, PI3K/Akt/eNOS pathway = Phosphatidylinositol 3-kinase/Protein kinase B/endothelial nitric oxide synthase pathway, eNOS = endothelial nitric oxide synthase, P = phosphorylation, BH<sub>4</sub> = tetrahydrobiopterin, NO = nitric oxide, ADP = adenosine diphosphate, ATP = adenosine triphosphate, CK = creatine kinase, VSMC = vascular smooth muscle cell, Na<sup>+</sup>/K<sup>+</sup> Pump = sodium/potassium pump, KATP = ATP-sensitive potassium pump, EDHF = endothelium-derived hyperpolarization factor, ↓ = decrease/reduction in, ↑ = increase in, “blue dashed line” = proposed pathway by Ahsan et al. \[<a href="#B147-nutrients-13-00857" class="html-bibr">147</a>\], phosphorylation and stimulation of eNOS.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/857'>Full article</a></strong>
                                        ")

17 pages, 3062 KiB   [ __](/2072-6643/13/3/751/pdf?version=1614591497 "Article PDF")

Open AccessReview

[The Role of Creatine in the Development and Activation of Immune Responses](/2072-6643/13/3/751)

by **Eric C. Bredahl** , **Joan M. Eckerson** , **Steven M. Tracy** , **Thomas L. McDonald** and **Kristen M. Drescher**

_Nutrients_ **2021** , _13_(3), 751; <https://doi.org/10.3390/nu13030751> \- 26 Feb 2021 

[Cited by 19](/2072-6643/13/3/751#metrics) | Viewed by 11925 

**Abstract**

The use of dietary supplements has become increasingly common over the past 20 years. Whereas supplements were formerly used mainly by elite athletes, age and fitness status no longer dictates who uses these substances. Indeed, many nutritional supplements are recommended by health care  [...] Read more.

The use of dietary supplements has become increasingly common over the past 20 years. Whereas supplements were formerly used mainly by elite athletes, age and fitness status no longer dictates who uses these substances. Indeed, many nutritional supplements are recommended by health care professionals to their patients. Creatine (CR) is a widely used dietary supplement that has been well-studied for its effects on performance and health. CR also aids in recovery from strenuous bouts of exercise by reducing inflammation. Although CR is considered to be very safe in recommended doses, a caveat is that a preponderance of the studies have focused upon young athletic individuals; thus there is limited knowledge regarding the effects of CR on children or the elderly. In this review, we examine the potential of CR to impact the host outside of the musculoskeletal system, specifically, the immune system, and discuss the available data demonstrating that CR can impact both innate and adaptive immune responses, together with how the effects on the immune system might be exploited to enhance human health. [Full article](/2072-6643/13/3/751)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g001-550.jpg?1614591573 "
                    <strong>Figure 1</strong><br/>
                                            <p>The creatine transporter. The creatine transporter \(green\) shuttles creatine from the extracellular space into the cytoplasm of the cell and is comprised of 12 transmembrane domains. Creatine kinase catalyzes a reversible reaction between creatine and phosphocreatine, resulting in the generation of ATP. NH2 = amine terminus, COOH = carboxy terminus.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g002-550.jpg?1614591573 "
                    <strong>Figure 2</strong><br/>
                                            <p>TLR expression under control and creatine-stimulated conditions. \(<b>A</b>\) Under normal conditions, TLRs are highly expressed on the cell surface or within the endosome. The sensing domain \(green\) of the TLR is located outside the cell or within the endosome. There is a transmembrane domain that spans the cell membrane \(red\) and the signaling domain \(maroon\) is located within the cytoplasm. \(<b>B</b>\) In the presence of creatine, TLR expression is downregulated by the cells.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g003-550.jpg?1614591573 "
                    <strong>Figure 3</strong><br/>
                                            <p>M1 and M2 macrophages develop under different stimuli and perform unique functions in the host. \(<b>A</b>\) Macrophages polarize to the M1 phenotype under conditions that highly activate the cells, such as when LPS or IFN-γ is present in the microenvironment. M1 macrophages are highly phagocytic and produce large amounts of proinflammatory mediators including TNF-α, IL-12, and IL-6. \(<b>B</b>\) M2 macrophages develop when IL-4 is present in the microenvironment. Cells of the M2 subtype produce mediators that are involved in tissue repair and angiogenesis. These cells produce large amounts IL-10, CCL17, CCL22 and arginase-1. In the presence of creatine, the polarization shifts towards an M2 phenotype.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g004-550.jpg?1614591573 "
                    <strong>Figure 4</strong><br/>
                                            <p>Creatine reduces inflammation to control levels. \(<b>A</b>\) In the absence of infection, there is no adhesion molecule expression on the vascular endothelium and neutrophils are not recruited into the tissue. \(<b>B</b>\) When the host is injured or infected, there is increased production of proinflammatory mediators that recruit immune cells \(IL-8\) and induce the expression of adhesion molecules on the vascular endothelium \(TNF-α, IL-1β\). Together, these mediators also induce swelling and loosen the interactions between the endothelial cells. These changes permit neutrophils \(and eventually other immune cells\) to be recruited to the site of damage/infection. \(<b>C</b>\) Creatine reduces inflammation, downregulates adhesion molecule and cytokine expression, and preserves the tight junctions in the endothelial cells to reduce inflammation.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g005-550.jpg?1614591573 "
                    <strong>Figure 5</strong><br/>
                                            <p>Creatine kinase B \(CKB\) levels vary during T cell development. Triple positive T cells in the cortex express low levels of CKB.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g006-550.jpg?1614591573 "
                    <strong>Figure 6</strong><br/>
                                            <p>Slc6a8 is required to control tumors. In normal mice with tumors, the tumor \(red\) is infiltrated by high levels of CD8+ T cells \(left\). The isolation and in vitro activation of these CD8+ T cells demonstrate that the cells produce large amounts of IL-2 and IFN-γ and express high levels of CD25 \(the high affinity IL-2 receptor\) and granzyme. In Slc6a8 knockout mice \(right\), the tumor is poorly controlled and the CD8+ T cells produce low levels of IL-2, IFN-γ, CD25, and granzyme following in vitro activation.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00751/article_deploy/html/images/nutrients-13-00751-g007-550.jpg?1614591573 "
                    <strong>Figure 7</strong><br/>
                                            <p>Effect of creatine on the development of disease in a mouse model of asthma. In the absence of creatine supplementation \(left lobe of lung\), asthma induction results in the recruitment of eosinophils to the airways, with IL-4, IL-5, and IGF-1 detected in the bronchoalveolar lavage fluid. Creatine supplementation \(right lobe of lung\) resulted in increased levels of these soluble mediators, as well as the increased production of CCL-2 and CCL-5 by endothelial cells, resulting in the increased recruitment of monocytes, lymphocytes, dendritic cells \(CCL2\) and eosinophils \(CCL5\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/751'>Full article</a></strong>
                                        ")

18 pages, 1199 KiB   [ __](/2072-6643/13/3/745/pdf?version=1615457471 "Article PDF")

Open AccessFeature PaperReview

[Current Evidence and Possible Future Applications of Creatine Supplementation for Older Adults](/2072-6643/13/3/745)

by **Darren G. Candow** , **Scott C. Forbes** , **Ben Kirk** and **Gustavo Duque**

_Nutrients_ **2021** , _13_(3), 745; <https://doi.org/10.3390/nu13030745> \- 26 Feb 2021 

[Cited by 32](/2072-6643/13/3/745#metrics) | Viewed by 18734 

**Abstract**

Sarcopenia, defined as age-related reduction in muscle mass, strength, and physical performance, is associated with other age-related health conditions such as osteoporosis, osteosarcopenia, sarcopenic obesity, physical frailty, and cachexia. From a healthy aging perspective, lifestyle interventions that may help overcome characteristics and associated  [...] Read more.

Sarcopenia, defined as age-related reduction in muscle mass, strength, and physical performance, is associated with other age-related health conditions such as osteoporosis, osteosarcopenia, sarcopenic obesity, physical frailty, and cachexia. From a healthy aging perspective, lifestyle interventions that may help overcome characteristics and associated comorbidities of sarcopenia are clinically important. One possible intervention is creatine supplementation (CR). Accumulating research over the past few decades shows that CR, primarily when combined with resistance training (RT), has favourable effects on aging muscle, bone and fat mass, muscle and bone strength, and tasks of physical performance in healthy older adults. However, research is very limited regarding the efficacy of CR in older adults with sarcopenia or osteoporosis and no research exists in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia. Therefore, the purpose of this narrative review is (1) to evaluate and summarize current research involving CR, with and without RT, on properties of muscle and bone in older adults and (2) to provide a rationale and justification for future research involving CR in older adults with osteosarcopenia, sarcopenic obesity, physical frailty, or cachexia. [Full article](/2072-6643/13/3/745)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00745/article_deploy/html/images/nutrients-13-00745-g001-550.jpg?1615802454 "
                    <strong>Figure 1</strong><br/>
                                            <p>Relative changes in femoral neck bone mineral density \(BMD\). “Closed diamonds” represent changes for individual creatine group participants, and “open circles” represent placebo group participants. The “horizontal bars” represent the group means, and the “vertical bars” represent the SD. * Creatine participants lost significantly less BMD at the femoral neck compared with placebo participants \(<span class="html-italic">p</span> &lt; 0.05\). \(Reproduced with permission from Chilibeck et al. 2015 \[<a href="#B28-nutrients-13-00745" class="html-bibr">28</a>\]\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/745'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00745/article_deploy/html/images/nutrients-13-00745-g002-550.jpg?1615802454 "
                    <strong>Figure 2</strong><br/>
                                            <p>Potential effect of creatine, with and without resistance training.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/3/745'>Full article</a></strong>
                                        ")

17 pages, 628 KiB   [ __](/2072-6643/13/2/664/pdf?version=1614233600 "Article PDF")

Open AccessReview

[Creatine Supplementation in Children and Adolescents](/2072-6643/13/2/664)

by **Andrew R. Jagim** and **Chad M. Kerksick**

_Nutrients_ **2021** , _13_(2), 664; <https://doi.org/10.3390/nu13020664> \- 18 Feb 2021 

[Cited by 26](/2072-6643/13/2/664#metrics) | Viewed by 33889 

**Abstract**

Creatine is a popular ergogenic aid among athletic populations with consistent evidence indicating that creatine supplementation also continues to be commonly used among adolescent populations. In addition, the evidence base supporting the therapeutic benefits of creatine supplementation for a plethora of clinical applications  [...] Read more.

Creatine is a popular ergogenic aid among athletic populations with consistent evidence indicating that creatine supplementation also continues to be commonly used among adolescent populations. In addition, the evidence base supporting the therapeutic benefits of creatine supplementation for a plethora of clinical applications in both adults and children continues to grow. Among pediatric populations, a strong rationale exists for creatine to afford therapeutic benefits pertaining to multiple neuromuscular and metabolic disorders, with preliminary evidence for other subsets of clinical populations as well. Despite the strong evidence supporting the efficacy and safety of creatine supplementation among adult populations, less is known as to whether similar physiological benefits extend to children and adolescent populations, and in particular those adolescent populations who are regularly participating in high-intensity exercise training. While limited in scope, studies involving creatine supplementation and exercise performance in adolescent athletes generally report improvements in several ergogenic outcomes with limited evidence of ergolytic properties and consistent reports indicating no adverse events associated with supplementation. The purpose of this article is to summarize the rationale, prevalence of use, performance benefits, clinical applications, and safety of creatine use in children and adolescents. [Full article](/2072-6643/13/2/664)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


10 pages, 648 KiB   [ __](/2072-6643/13/2/586/pdf?version=1612961973 "Article PDF")

Open AccessReview

[Creatine Supplementation and Brain Health](/2072-6643/13/2/586)

by **Hamilton Roschel** , **Bruno Gualano** , **Sergej M. Ostojic** and **Eric S. Rawson**

_Nutrients_ **2021** , _13_(2), 586; <https://doi.org/10.3390/nu13020586> \- 10 Feb 2021 

[Cited by 84](/2072-6643/13/2/586#metrics) | Viewed by 78117 

**Abstract**

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing,  [...] Read more.

There is a robust and compelling body of evidence supporting the ergogenic and therapeutic role of creatine supplementation in muscle. Beyond these well-described effects and mechanisms, there is literature to suggest that creatine may also be beneficial to brain health (e.g., cognitive processing, brain function, and recovery from trauma). This is a growing field of research, and the purpose of this short review is to provide an update on the effects of creatine supplementation on brain health in humans. There is a potential for creatine supplementation to improve cognitive processing, especially in conditions characterized by brain creatine deficits, which could be induced by acute stressors (e.g., exercise, sleep deprivation) or chronic, pathologic conditions (e.g., creatine synthesis enzyme deficiencies, mild traumatic brain injury, aging, Alzheimer’s disease, depression). Despite this, the optimal creatine protocol able to increase brain creatine levels is still to be determined. Similarly, supplementation studies concomitantly assessing brain creatine and cognitive function are needed. Collectively, data available are promising and future research in the area is warranted. [Full article](/2072-6643/13/2/586)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00586/article_deploy/html/images/nutrients-13-00586-g001-550.jpg?1613178347 "
                    <strong>Figure 1</strong><br/>
                                            <p>Dietary creatine is transported through the blood–brain barrier via a creatine transporter. Astrocytes cells can also endogenously produce creatine, which is taken up by the neurons expressing the creatine transporter. Cr: creatine; PCr: phosphocreatine; Gly: glycine; Arg: arginine; AGAT: L-ariginine: glycine amidinotransferase; GAA: guanidinoacetate; GAMT: guanidinoacetate methyltransferase, SAM: S-adenosylmethionine; CreaT: Cr transporter. Created with BioRender.com.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/586'>Full article</a></strong>
                                        ")

13 pages, 590 KiB   [ __](/2072-6643/13/2/570/pdf?version=1612939104 "Article PDF")

Open AccessReview

[Potential of Creatine in Glucose Management and Diabetes](/2072-6643/13/2/570)

by **Marina Yazigi Solis** , **Guilherme Giannini Artioli** and **Bruno Gualano**

_Nutrients_ **2021** , _13_(2), 570; <https://doi.org/10.3390/nu13020570> \- 9 Feb 2021 

[Cited by 26](/2072-6643/13/2/570#metrics) | Viewed by 26282 

**Abstract**

Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a  [...] Read more.

Creatine is one of the most popular supplements worldwide, and it is frequently used by both athletic and non-athletic populations to improve power, strength, muscle mass and performance. A growing body of evidence has been identified potential therapeutic effects of creatine in a wide variety of clinical conditions, such as cancer, muscle dystrophy and neurodegenerative disorders. Evidence has suggested that creatine supplementation alone, and mainly in combination with exercise training, may improve glucose metabolism in health individuals and insulin-resistant individuals, such as in those with type 2 diabetes mellitus. Creatine itself may stimulate insulin secretion in vitro, improve muscle glycogen stores and ameliorate hyperglycemia in animals. In addition, exercise induces numerous metabolic benefits, including increases in insulin-independent muscle glucose uptake and insulin sensitivity. It has been speculated that creatine supplementation combined with exercise training could result in additional improvements in glucose metabolism when compared with each intervention separately. The possible mechanism underlying the effects of combined exercise and creatine supplementation is an enhanced glucose transport into muscle cell by type 4 glucose transporter (GLUT-4) translocation to sarcolemma. Although preliminary findings from small-scale trials involving patients with type 2 diabetes mellitus are promising, the efficacy of creatine for improving glycemic control is yet to be confirmed. In this review, we aim to explore the possible therapeutic role of creatine supplementation on glucose management and as a potential anti-diabetic intervention, summarizing the current knowledge and highlighting the research gaps. [Full article](/2072-6643/13/2/570)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00570/article_deploy/html/images/nutrients-13-00570-g001-550.jpg?1612939170 "
                    <strong>Figure 1</strong><br/>
                                            <p>Possible creatine-related mechanisms on glycemic control. Potential mechanisms underpinning the role of creatine on glucose metabolism involve: \(1\) increased beta-cell insulin secretion; \(2\) improved water retention and osmosensing genes and \(3\) increased glucose uptake via type 4 glucose transporter \(GLUT-4\) content and activity. Additionally, \(4\) creatine supplementation could enhance the known benefits of exercise on glucose uptake/insulin sensitivity. There are currently insufficient clinical data to support all of these mechanisms. Note: Cr: creatine; CreaT: creatine transporter; IR: insulin receptor; GLUT-4: glucose transporter; PKBa/Akt1: protein kinase Bα; AMPK: Adenosine Monophosphate-activated protein kinase.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/570'>Full article</a></strong>
                                        ")

9 pages, 494 KiB   [ __](/2072-6643/13/2/503/pdf?version=1612412114 "Article PDF")

Open AccessReview

[Diagnostic and Pharmacological Potency of Creatine in Post-Viral Fatigue Syndrome](/2072-6643/13/2/503)

by **Sergej M. Ostojic**

_Nutrients_ **2021** , _13_(2), 503; <https://doi.org/10.3390/nu13020503> \- 4 Feb 2021 

[Cited by 14](/2072-6643/13/2/503#metrics) | Viewed by 14362 

**Abstract**

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue  [...] Read more.

Post-viral fatigue syndrome (PVFS) is a widespread chronic neurological disease with no definite etiological factor(s), no actual diagnostic test, and no approved pharmacological treatment, therapy, or cure. Among other features, PVFS could be accompanied by various irregularities in creatine metabolism, perturbing either tissue levels of creatine in the brain, the rates of phosphocreatine resynthesis in the skeletal muscle, or the concentrations of the enzyme creatine kinase in the blood. Furthermore, supplemental creatine and related guanidino compounds appear to impact both patient- and clinician-reported outcomes in syndromes and maladies with chronic fatigue. This paper critically overviews the most common disturbances in creatine metabolism in various PVFS populations, summarizes human trials on dietary creatine and creatine analogs in the syndrome, and discusses new frontiers and open questions for using creatine in a post-COVID-19 world. [Full article](/2072-6643/13/2/503)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Figure 1

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00503/article_deploy/html/images/nutrients-13-00503-g001-550.jpg?1612412181 "
                    <strong>Figure 1</strong><br/>
                                            <p>Possible mechanisms of creatine action in post-viral fatigue syndrome.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/503'>Full article</a></strong>
                                        ")

23 pages, 970 KiB   [ __](/2072-6643/13/2/490/pdf?version=1612342757 "Article PDF")

Open AccessReview

[Creatine Metabolism in Female Reproduction, Pregnancy and Newborn Health](/2072-6643/13/2/490)

by **Anna Maria Muccini** , **Nhi T. Tran** , **Deborah L. de Guingand** , **Mamatha Philip** , **Paul A. Della Gatta** , **Robert Galinsky** , **Larry S. Sherman** , **Meredith A. Kelleher** , **Kirsten R. Palmer** , **Mary J. Berry** , **David W. Walker** , **Rod J. Snow** and **Stacey J. Ellery**

_Nutrients_ **2021** , _13_(2), 490; <https://doi.org/10.3390/nu13020490> \- 2 Feb 2021 

[Cited by 48](/2072-6643/13/2/490#metrics) | Viewed by 17120 

**Abstract**

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or  [...] Read more.

Creatine metabolism is an important component of cellular energy homeostasis. Via the creatine kinase circuit, creatine derived from our diet or synthesized endogenously provides spatial and temporal maintenance of intracellular adenosine triphosphate (ATP) production; this is particularly important for cells with high or fluctuating energy demands. The use of this circuit by tissues within the female reproductive system, as well as the placenta and the developing fetus during pregnancy is apparent throughout the literature, with some studies linking perturbations in creatine metabolism to reduced fertility and poor pregnancy outcomes. Maternal dietary creatine supplementation during pregnancy as a safeguard against hypoxia-induced perinatal injury, particularly that of the brain, has also been widely studied in pre-clinical in vitro and small animal models. However, there is still no consensus on whether creatine is essential for successful reproduction. This review consolidates the available literature on creatine metabolism in female reproduction, pregnancy and the early neonatal period. Creatine metabolism is discussed in relation to cellular bioenergetics and de novo synthesis, as well as the potential to use dietary creatine in a reproductive setting. We highlight the apparent knowledge gaps and the research “road forward” to understand, and then utilize, creatine to improve reproductive health and perinatal outcomes. [Full article](/2072-6643/13/2/490)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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![](data:image/gif;base64,R0lGODlhAQABAAD/ACwAAAAAAQABAAACADs=)

Graphical abstract

[](https://pub.mdpi-res.com/nutrients/nutrients-13-00490/article_deploy/html/images/nutrients-13-00490-ag-550.jpg?1612343674 "
                    <strong>Graphical abstract</strong><br/><strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/490'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00490/article_deploy/html/images/nutrients-13-00490-g001-550.jpg?1612343674 "
                    <strong>Figure 1</strong><br/>
                                            <p>The creatine kinase circuit. Creatine can be produced endogenously by some cells or taken up from the circulation via the creatine transporter \(<span class="html-italic">SLC6A8</span>\). Creatine is then phosphorylated from adenosine triphosphate \(ATP\) to form phosphocreatine and adenosine diphosphate \(ADP\) in a reaction catalyzed by ubiquitous mitochondrial creatine kinase \(uMt-CK\). Isoforms of creatine kinase in the cell cytosol \(mainly brain-type creatine kinase CKBB\) are also linked to glycolytic enzymes \(G\) to generate phosphocreatine and ADP from glycolytic ATP. Then, when required for energy-dependent cellular processes, cytosolic isoforms of creatine kinase \(CKBB\) hydrolyze the bond between creatine and the phosphate group stored as phosphocreatine, thus regenerating ATP and creatine. Note: muscle-type cytosolic creatine kinase \(CKMM\) expression has also been detected in mouse oocytes.</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/490'>Full article</a></strong>
                                        ")[](https://pub.mdpi-res.com/nutrients/nutrients-13-00490/article_deploy/html/images/nutrients-13-00490-g002-550.jpg?1612343674 "
                    <strong>Figure 2</strong><br/>
                                            <p>Schematic of de novo creatine synthesis. Step one—Arginine and glycine combine to form guanidinoacetic acid \(GAA\) and ornithine in a reaction catalyzed by arginine:glycine amidinotransferase \(AGAT translated from the <span class="html-italic">GATM</span> gene\). Step two—GAA is methylated to form creatine and S-Adenosyl homocysteine. S-adenosyl methionine \(SAM\) is the primary methyl donor for this reaction catalyzed by guanidinoacetate methyltransferase \(<span class="html-italic">GAMT</span>/GAMT\).</p>
                                                                <strong style='display: block; margin-top: 10px; font-size: 18px;'><a style='color: #fff' href='/2072-6643/13/2/490'>Full article</a></strong>
                                        ")

27 pages, 515 KiB   [ __](/2072-6643/13/2/447/pdf?version=1612326917 "Article PDF")

Open AccessEditor’s ChoiceReview

[Creatine in Health and Disease](/2072-6643/13/2/447)

by **Richard B. Kreider** and **Jeffery R. Stout**

_Nutrients_ **2021** , _13_(2), 447; <https://doi.org/10.3390/nu13020447> \- 29 Jan 2021 

[Cited by 96](/2072-6643/13/2/447#metrics) | Viewed by 64244 

**Abstract**

Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in  [...] Read more.

Although creatine has been mostly studied as an ergogenic aid for exercise, training, and sport, several health and potential therapeutic benefits have been reported. This is because creatine plays a critical role in cellular metabolism, particularly during metabolically stressed states, and limitations in the ability to transport and/or store creatine can impair metabolism. Moreover, increasing availability of creatine in tissue may enhance cellular metabolism and thereby lessen the severity of injury and/or disease conditions, particularly when oxygen availability is compromised. This systematic review assesses the peer-reviewed scientific and medical evidence related to creatine’s role in promoting general health as we age and how creatine supplementation has been used as a nutritional strategy to help individuals recover from injury and/or manage chronic disease. Additionally, it provides reasonable conclusions about the role of creatine on health and disease based on current scientific evidence. Based on this analysis, it can be concluded that creatine supplementation has several health and therapeutic benefits throughout the lifespan. [Full article](/2072-6643/13/2/447)

(This article belongs to the Special Issue [Creatine Supplementation for Health and Clinical Diseases](        
    /journal/nutrients/special_issues/creatine_supplementation
))  


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url: http://arxiv.org/abs/2307.02463v1
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[2307.02463v1] An Euler-Bernoulli-Type Beam Model of the Vocal Folds for Describing Curved and Incomplete Glottal Closure Patterns

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# Physics > Medical Physics

**arXiv:2307.02463v1** (physics) 

[Submitted on 5 Jul 2023]

# Title:An Euler-Bernoulli-Type Beam Model of the Vocal Folds for Describing Curved and Incomplete Glottal Closure Patterns

Authors:[Mohamed A. Serry](https://arxiv.org/search/physics?searchtype=author&query=Serry,+M+A), [Gabriel A. Alzamendi](https://arxiv.org/search/physics?searchtype=author&query=Alzamendi,+G+A), [Matías Zañartu](https://arxiv.org/search/physics?searchtype=author&query=Za%C3%B1artu,+M), [Sean D. Peterson](https://arxiv.org/search/physics?searchtype=author&query=Peterson,+S+D)

View a PDF of the paper titled An Euler-Bernoulli-Type Beam Model of the Vocal Folds for Describing Curved and Incomplete Glottal Closure Patterns, by Mohamed A. Serry and 3 other authors

[View PDF](/pdf/2307.02463v1)

> Abstract:Incomplete glottal closure is a laryngeal configuration wherein the glottis is not fully obstructed prior to phonation. In this work, we introduce an Euler-Bernoulli composite beam vocal fold (VF) model that produces qualitatively similar incomplete glottal closure patterns as those observed in experimental and high-fidelity numerical studies, thus offering insights in to the potential underlying physical mechanisms. Refined physiological insights are pursued by incorporating the beam model into a VF posturing model that embeds the five intrinsic laryngeal muscles. Analysis of the combined model shows that co-activating the lateral cricoarytenoid (LCA) and interarytenoid (IA) muscles without activating the thyroarytenoid (TA) muscle results in a bowed (convex) VF geometry with closure at the posterior margin only; this is primarily attributed to the reactive moments at the anterior VF margin. This bowed pattern can also arise during VF compression (due to extrinsic laryngeal muscle activation for example), wherein the internal moment induced passively by the TA muscle tissue is the predominant mechanism. On the other hand, activating the TA muscle without incorporating other adductory muscles results in anterior and mid-membranous glottal closure, a concave VF geometry, and a posterior glottal opening driven by internal moments induced by TA muscle activation. In the case of initial full glottal closure, the posterior cricoarytenoid (PCA) muscle activation cancels the adductory effects of the LCA and IA muscles, resulting in a concave VF geometry and posterior glottal opening. Furthermore, certain maneuvers involving co-activation of all adductory muscles result in an hourglass glottal shape due to a reactive moment at the anterior VF margin and moderate internal moment induced by TA muscle activation. 

Subjects: |  Medical Physics (physics.med-ph)  
---|---  
Cite as: | [arXiv:2307.02463](https://arxiv.org/abs/2307.02463) [physics.med-ph]  
  | (or  [arXiv:2307.02463v1](https://arxiv.org/abs/2307.02463v1) [physics.med-ph] for this version)   
  |  <https://doi.org/10.48550/arXiv.2307.02463> Focus to learn more arXiv-issued DOI via DataCite  
  
## Submission history

From: Mohamed Serry [[view email](/show-email/ff830319/2307.02463)]   
**[v1]** Wed, 5 Jul 2023 17:36:44 UTC (356 KB)  


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url: http://arxiv.org/abs/2406.16433v1
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hash: 36de962246ffc78cf51529c5c20c05a40d7c767373da340425b9288b387c31c0
title:
[2406.16433v1] Multiscale Mechanical Modeling of Skeletal Muscle: A Systemic Review of the Literature

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# Physics > Medical Physics

**arXiv:2406.16433v1** (physics) 

[Submitted on 24 Jun 2024]

# Title:Multiscale Mechanical Modeling of Skeletal Muscle: A Systemic Review of the Literature

Authors:[Aude Loumeaud](https://arxiv.org/search/physics?searchtype=author&query=Loumeaud,+A) (ICube, BMBI), [Philippe Pouletaut](https://arxiv.org/search/physics?searchtype=author&query=Pouletaut,+P) (BMBI), [Sabine Bensamoun](https://arxiv.org/search/physics?searchtype=author&query=Bensamoun,+S) (BMBI), [Daniel George](https://arxiv.org/search/physics?searchtype=author&query=George,+D) (ICube), [Simon Chatelin](https://arxiv.org/search/physics?searchtype=author&query=Chatelin,+S) (ICube)

View a PDF of the paper titled Multiscale Mechanical Modeling of Skeletal Muscle: A Systemic Review of the Literature, by Aude Loumeaud (ICube and 5 other authors

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> Abstract:Purpose: From the myofibrils to the whole muscle scale, muscle micro-constituents exhibit passive and active mechanical properties, potentially coupled to electrical, chemical, and thermal properties. Experimental characterization of some of these properties is currently not available for all muscle constituents. Multiscale multiphysics models have recently gained interest as a numerical alternative to investigate the healthy and diseased physiological behavior of the skeletal muscle. Methods: This paper refers to the multiscale mechanical models proposed in the literature to investigate the mechanical properties and behavior of skeletal muscles. More specifically, we focus on the scale transition methods, constitutive laws and experimental data implemented in these models. Results: Using scale transition methods such as homogenization, coupled to appropriate constitutive behavior of the constituents, these models explore the mechanisms of ageing, myopathies, sportive injuries, and muscle contraction. Conclusion: Emerging trends include the development of multiphysics simulations and the coupling of modeling with the acquisition of experimental data at different scales, with increasing focus to little known constituents such as the extracellular matrix and the protein titin. 

Comments: | Journal of Medical and Biological Engineering, 2024  
---|---  
Subjects: |  Medical Physics (physics.med-ph)  
Cite as: | [arXiv:2406.16433](https://arxiv.org/abs/2406.16433) [physics.med-ph]  
  | (or  [arXiv:2406.16433v1](https://arxiv.org/abs/2406.16433v1) [physics.med-ph] for this version)   
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## Submission history

From: Simon Chatelin [[view email](/show-email/8c473f89/2406.16433)] [via CCSD proxy]   
**[v1]** Mon, 24 Jun 2024 08:26:48 UTC (856 KB)  


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# The Body weight Reducing Effects of Tirzepatide in People with and without Type 2 Diabetes: A Review on Efficacy and Adverse Effects

[Thomas Leth Jensen](https://pubmed.ncbi.nlm.nih.gov/?term=%22Jensen%20TL%22%5BAuthor%5D)

### Thomas Leth Jensen

1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

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1, [Andreas Brønden](https://pubmed.ncbi.nlm.nih.gov/?term=%22Br%C3%B8nden%20A%22%5BAuthor%5D)

### Andreas Brønden

1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

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1, [Kristian Karstoft](https://pubmed.ncbi.nlm.nih.gov/?term=%22Karstoft%20K%22%5BAuthor%5D)

### Kristian Karstoft

1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark

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1,2, [David Peick Sonne](https://pubmed.ncbi.nlm.nih.gov/?term=%22Sonne%20DP%22%5BAuthor%5D)

### David Peick Sonne

1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark

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1,2, [Mikkel Bring Christensen](https://pubmed.ncbi.nlm.nih.gov/?term=%22Christensen%20MB%22%5BAuthor%5D)

### Mikkel Bring Christensen

1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark

3Center for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

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1,2,3,✉

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1Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

2Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark

3Center for Translational Research, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, DK-2400, Denmark

✉

Correspondence: Mikkel Bring Christensen, Email Mikkel.bring.christensen@regionh.dk

Received 2023 Oct 3; Accepted 2024 Jan 17; Collection date 2024.

© 2024 Jensen et al.

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PMCID: PMC10861994 PMID: [38352159](https://pubmed.ncbi.nlm.nih.gov/38352159/)

## Abstract

Obesity is becoming more frequent and has several negative health impacts. Recent advances in weight management strategies have primarily resided in pharmaceutical treatments, and the glucagon-like peptide-1 (GLP-1) receptor agonists have shown great potential in terms of body weight reduction in addition to improving glycemic control in patients with type 2 diabetes (T2D). Recently, the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide has been developed. Tirzepatide has shown strong effects on glycated hemoglobin (HbA1C) levels in several clinical trials including participants with T2D (SURPASS program). In addition to its lowering effect on HbA1C, tirzepatide leads to substantial reductions in body weight, and a series of clinical trials (SURMOUNT program) have investigated the effects on body weight as the primary outcome. In these two trial programs, tirzepatide in doses of 5 mg to 15 mg administered subcutaneously once weekly resulted in body weight reduction of up to 15% in participants with T2D and up to 21% in participants without T2D, despite comparable baseline bodyweight. Across the two trial programs, adverse effects were mainly gastrointestinal (nausea, diarrhea, and vomiting) occurring with similar incidences of vomiting and lower incidences of diarrhea and nausea in trial participants with T2D compared to trials participants without T2D. Overall, discontinuation due to adverse events occurred in 3–7% of participants with no major differences between individuals with and without T2D. The higher weight-reducing efficacy of tirzepatide in trial participants without T2D is currently unexplained and may be partly reflected in dissimilarities in frequencies of gastrointestinal adverse events. The weight reducing effects of tirzepatide hold great promise for weight management in obese patients regardless of the presence of T2D.

**Keywords:** tirzepatide, weight loss, type 2 diabetes, GLP-1, GIP, dual agonists, safety

## Introduction

Obesity, defined by the World Obesity Federation as having a body mass index (BMI) ≥30, is becoming increasingly prevalent with an expected rise from 14% of the global population in 2023 up to 24% of the global population by 2035. Thus, 2 billion people globally are expected to be obese by 2035.1 Obesity has an impact on morbidity and mortality and results inweight-related complications resulting in reduced quality of life for patients, and obesity increases the risk of developing type 2 diabetes (T2D), cardiovascular diseases and certain types of cancer.1,2 According to current trends extrapolating the severe detrimental effects of obesity on health, it has been estimated that overweight and obesity gave rise to a lost income of almost 2 trillion USD on a global scale in 2020, a number expected to rise to over 4 trillion USD in 2035.1

Recent advances in the treatment of obesity include refinement of bariatric surgery, improved efficacy of lifestyle and behavioral interventions, and novel weight-loss medications.2 For many years pharmacological options were limited to compounds with very sparse efficacy (eg, orlistat eliciting <6 kg weight loss after 4 years).3 Recent advancements in weight-loss medications have largely centered around harnessing the physiological effects of the incretin hormones. The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) amplify insulin secretion in a glucose-dependent manner, and furthermore, GLP-1 has been demonstrated to reduce appetite and food ingestion. This has given rise to the development of GLP-1 receptor agonists that were initially approved for the treatment of T2D, and which have now been approved for the treatment of obesity.4,5 While early GLP-1 receptor agonists showed weight loss in the range of 5% compared with placebo, newer drugs with more continuous activation of the GLP-1 receptor have elicited body weight reductions of up to 15% from baseline.6,7 Currently, the GLP-1 receptor mono-agonists liraglutide and semaglutide have both been approved for the treatment of T2D as well as obesity.8,9

Based on the beneficial potential of GLP-1 receptor agonists, development of dual-agonists (a single molecule with agonistic effect on two different receptors) has included development of drugs with co-agonism at the GLP-1 and/or GIP receptors as well as the glucagon receptor.10 Tirzepatide, a dual-agonist targeting GIP and GLP-1 receptors, had a pronounced effect on body weight reductions in preclinical trials compared to established GLP-1 receptor mono-agonists.5,11 Tirzepatide has shown strong effects on glycated hemoglobin (HbA1C) as a primary outcome in a range of clinical trials (SURPASS program). In addition, several clinical trials have investigated the effects of tirzepatide specifically for the treatment of obesity (SURMOUNT program). Tirzepatide is now approved for treatment of T2D in both the US and in Europe (tradename: Mounjaro®), and in the US for chronic weight management in adults with obesity or overweight and at least one weight-related condition (tradename: Zepbound®).12–14

This review summarizes the effects of the GLP-1 and GIP dual-agonist tirzepatide on weight loss alongside the safety profile of this compound, with a specific focus on differences between patients with and without T2D.

## Tirzepatide

Tirzepatide is a dual-agonist molecule that activates both the GLP-1 and the GIP receptor and is administered subcutaneously (s.c.) once weekly.15 Tirzepatide binds to the GLP-1 receptor with a 20% affinity compared with native GLP-1 and activates the receptor (measured by cAMP generation) with a 20-fold lower potency. In comparison, the GLP-1 agonist semaglutide binds to the GLP-1 receptor with a 60% affinity of that of native GLP-1. The affinity and potency of tirzepatide on the GIP receptor is similar to that of native human GIP.16,17 Tirzepatide consists of a single molecule with a linear 39 amino acid peptide backbone with an acyl fat-chain conjugation to enhance albumin binding and prolong half-life.18 The bioavailability of tirzepatide is 81% and the maximum plasma concentration is reached 48 hours (range: 12–96 hours) after administration.12,19,20 The half-life of tirzepatide is 117 hours and it is eliminated by proteolytic cleavage, amide hydrolysis and β-oxidation, while the cytochrome P450 enzymes are not involved in elimination. Neither hepatic nor renal impairment substantially affect the pharmacokinetics of tirzepatide.12,16,17,19–21

## Clinical Data

Two clinical trial programs investigating the efficacy and safety of tirzepatide have been performed; one primarily evaluating efficacy on bodyweight (SURMOUNT) and another primarily evaluating the glucose-lowering efficacy (SURPASS). An overview of the SURMOUNT trials is shown in Table 1.22–27 The SURMOUNT-1 trial investigated the weight-reducing effect of tirzepatide in obese participants without T2D (of note 1032 out of 2539 participants had prediabetes defined as having a HbA1C of 5.7–6.4% (39–47 mmol/mol)). The SURMOUNT-2 trial (N = 938) investigated weight loss in participants with T2D and overweight (BMI > 27), and both trials investigated the effect of 10 mg and 15 mg s.c. once weekly doses of tirzepatide, while the SURMOUNT-1 trial also investigated the effect of 5 mg s.c. once weekly.26,27

### Table 1.

Overview of Studies in the SURMOUNT Trial Program

Title (Trial Abbreviation) | Number of Participants | Trial Type and Interventions | Duration | Baseline Age, Weight, BMI, Gender | Notable Inclusion/Exclusion Criteria | Primary Outcome  
---|---|---|---|---|---|---  
Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1) | 2539 | Randomized, double blind placebo controlled clinical trial.  
Interventions: Tirzepatide 5 mg, 10 mg, 15 mg s.c. once weekly, or placebo | 72 weeks | 44.7 years, 104.8 kg, BMI 38.0 kg/m2, 67.5% female | No T2D | Body weight (% change from baseline)  
Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes: a double-blind, randomized, multicenter, placebo-controlled, Phase 3 trial (SURMOUNT-2) | 938 | Randomized, double blind, placebo controlled clinical trial. Interventions: Tirzepatide 10 mg, 15 mg s.c. once weekly, or placebo | 72 weeks | 54.2 years, 100.7 kg, BMI 36.1 kg/m2, 51.0% female | T2D (mean duration 8.5 years) | Body weight (% change from baseline)  
**Ongoing trials and trials where results have not been published/published fully:**  
A study of tirzepatide (LY3298176) in participants after a lifestyle weight loss program (SURMOUNT-3) | 806 | Randomized, double blind, placebo controlled clinical trial  
Interventions:  
Tirzepatide 10 mg, 15 mg s.c. once weekly, or placebo | 72 weeks | N/A, 109.5 kg, N/A, N/A | No T2D | Body weight (% change from baseline after 72 weeks)  
A study of tirzepatide (LY3298176) in participants with obesity or overweight for the maintenance of weight loss (SURMOUNT-4) | 783 | Open label lead-in for 36 weeks followed by 52 weeks of randomized, double blind, placebo controlled clinical trial  
Interventions: Tirzepatide 10 mg, 15 mg s.c. once weekly, or placebo | 52 weeks | N/A, 107.3 kg, N/A, N/A | No T2D | Body weight (% change from baseline 52 weeks after randomization (following a lead-in phase of 36-weeks open label treatment))  
A study of tirzepatide (LY3298176) on the reduction on morbidity and mortality in adults with obesity (SURMOUNT-MMO) | 15,000 | Randomized, double blind, placebo controlled clinical trial Interventions: Tirzepatide*, Placebo | Up to 5 years | No data available (Trial ongoing, ending October 2027) | With or at high risk for cardiovascular disease, No T2D | Time to first occurrence of any component event of composite (all-cause death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or heart failure events)  
Obstructive sleep apnea master protocol GPIF: a study of tirzepatide (LY3298176) in participants with obstructive sleep apnea (SURMOUNT-OSA) | 469 | Randomized, double blind, placebo controlled clinical trial Interventions: Tirzepatide*, Placebo | 52 weeks | No data available (Trial ongoing, ending March 2024) | Obstructive sleep apnea, no T2D | Change from baseline in apnea-hypopnea index (AHI)  
  
[Open in a new tab](table/t0001/)

**Notes** : *Doses not listed on clinicaltrials.gov. Data from these studies22–27.

**Abbreviations** : BMI, body mass index; T2D, type 2 diabetes; s.c, subcutaneously.

The SURPASS clinical trial program included only participants with T2D and had mean change in HbA1C as the primary endpoint, whereas weight loss was reported as a secondary outcome. In the SURPASS-2 trial tirzepatide was compared to the GLP-1 agonist semaglutide 1 mg s.c. once weekly, and in the SURPASS J-Mono tirzepatide was compared to the GLP-1 agonist dulaglutide 0.75 mg s.c. once weekly. The SURPASS-1 trial examined tirzepatide as monotherapy while the remaining SURPASS trials applied tirzepatide as an add-on to other glucose-lowering therapies comprised by metformin, insulin, SGLT2 inhibitors, sulfonylurea, or a combination of these.28–35

## Body Weight

The SURMOUNT-1 trial, investigating doses of 5 mg, 10 mg, and 15 mg s.c. once weekly in individuals with obesity (BMI > 30.0 or BMI > 27 and weight-related complications) but no T2D, reported a reduction in bodyweight of up to 20.9% (treatment policy estimand) after 72 weeks of treatment with maximum dose of tirzepatide (15 mg s.c. once weekly), while placebo elicited a weight loss of 3.1%.27 The SURMOUNT-2 trial investigated doses of 10 mg and 15 mg s.c. once weekly in patients with overweight (BMI > 27) and T2D and reported a weight loss of 14.7% (treatment policy estimand) for the high-dose treatment arm after 72 weeks compared to a weight loss of 3.2% following placebo treatment.26

The SURPASS trials investigated the effect of tirzepatide in participants with T2D and reported weight reductions of 5–14%.28–35 The SURPASS-2 trial compared all doses of tirzepatide to 1 mg s.c. once weekly of semaglutide and reported that the 15 mg dose of tirzepatide on average resulted in an absolute reduction in body weight of 6.6% more than semaglutide.29

## Other Outcomes of Interest

Improvements in several metabolic markers have been reported following treatment with tirzepatide. The SURPASS trials reported reductions in HbA1C ranging from 20.4 mmol/mol (5 mg tirzepatide s.c. once weekly dose) to 28.2 mmol/mol (15 mg tirzepatide s.c. once weekly dose) after treatment durations lasting 40–52 weeks.28–35 Trials in Japanese populations reported even greater reductions in HbA1C (reduction of 33.0 mmol/mol in the 15 mg tirzepatide s.c. once weekly dose).34 Furthermore, reductions in systolic blood pressure of 4.7–12.6 mmHg and reductions in diastolic blood pressure of 0.8–5.6 mmHg were reported in the SURPASS trials. Total cholesterol was reduced by 2.2–15.4%, LDL was reduced by 5.3–19.3% (except for the SURMOUNT-2 trial that reported an increase of 2.3–3.2%) and HDL was increased by 0.9–10.8%.26–34 While these changes may be, in part, mediated by body weight reductions, they are nevertheless important improvements in measurable metabolic markers.22,23

Some important sub-group analyses have been performed to investigate other factors affected by treatment with tirzepatide. The SURPASS-1 trial reported a reduction in total body fat mass of 26% [95% confidence interval (CI): 20–31%] for all tirzepatide doses pooled (5 mg, 10 mg and 15 mg tirzepatide s.c. once weekly groups) compared to placebo.28 Magnetic resonance imaging (MRI) was performed for a subgroup in the SURPASS-3 trial to investigate changes in liver fat. In the SURPASS-3 trial, participants had an average T2D duration of 8.4 years, a mean BMI of 33.5 kg/m2, and were treated with metformin alone or in combination with an SGLT2 inhibitor. Participants in the MRI sub-study had a fatty liver index ≥60.30,36 An absolute reduction of 8.1% from a baseline liver fat content of 15.7% was demonstrated for pooled 10 mg and 15 mg s.c. once weekly tirzepatide groups, compared to an absolute reduction in liver fat content of 3.4% in participants treated with insulin degludec.36 Tirzepatide has shown reductions in both body fat mass and lean body mass.37 MRI analysis of body composition in a subset of participants from the SURPASS-3 study revealed a larger decrease in muscle fat infiltration than anticipated. However, it also indicated an overall reduction in fat-free muscle mass (−0.76 liters for the 15 mg s.c. once weekly group).38

Risk of major adverse cardiovascular events (MACE) was analyzed in a meta-analysis for all SURPASS trials and showed no statistically significant differences between pooled tirzepatide groups and control groups (hazard-ratio (HR) 0.80 [95% CI: 0.57–1.11]). The same study provided a meta-analysis of events of cardiovascular death and all-cause mortality in participants treated with tirzepatide and reported HRs of 0.90 [95% CI: 0.5–1.6] and 0.80 [95% CI: 0.51–1.3], respectively.39

## Clinical Safety

Tirzepatide has in clinical testing shown to be safe and relatively well tolerated with mild to moderate adverse effects that most frequently were of gastrointestinal nature. In early clinical testing (phase I and Phase II trials) a gradual dose escalation was implemented, which increased tolerability and reduced the frequency of adverse events (AEs).40,41 Thus, in the trial programs tirzepatide was started with a dose of 2.5 mg tirzepatide s.c. once weekly and followed by increases in dose of 2.5 mg every 4 weeks.

AEs in the SURMOUNT-1 trial (participants without T2D) were seen in up to 82% of participants, with 4–7% discontinuing the trial due to AEs (compared with 3% in the placebo group).27 In the SURMOUNT-2 trial (participants with T2D with a mean duration of 8.5 years), up to 78% of participants experienced AEs and 4–7% discontinued due to AEs (compared with 4% in the placebo group).26 Hypoglycemia (<3.0 mmol/L) was seen in up to 2% of participants without T2D (SURMOUNT-1) and up to 4% of participants with T2D, while no cases of severe hypoglycemia was reported in the SURMOUNT-1 or −2 trials.26,27 In patients treated with sulfonylurea at baseline in the SURPAS-4 trial, 9% of participants experienced hypoglycemia, while 19% of participants treated with both sulfonylurea and insulin glargine experienced hypoglycemia.31

Discontinuations due to AEs were primarily due to gastrointestinal events, and AEs were often reported in the dose-escalation phase and then decreased in frequency over time.19,32,34 Frequency of gastrointestinal adverse events in participants with and without T2D, as well as weight loss, is illustrated in Figure 1. The duration of diarrhea, nausea and vomiting was reported in the SURPASS-AP-Combo trial, a trial investigating the effect of tirzepatide in an Asian-Pacific population with T2D, in which the mean duration of these AEs were 3 days, 3–4 days, and 1–2 days, respectively.35 There was a similar frequency of gastrointestinal side-effects compared to semaglutide in the SURPASS-2 trial (1 mg s.c. once weekly).29

### Figure 1.

[![Figure 1](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/98e1/10861994/0fc12bcca016/PPA-18-373-g0001.jpg)](https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=10861994_PPA-18-373-g0001.jpg)

[Open in a new tab](figure/f0001/)

Comparisons of weight loss (% change in body weight from baseline) and frequency in percent of gastro-intestinal adverse events reported by participants with type 2 diabetes (Orange lines, pooled data from SURMOUNT-2 and SURPASS-3 trials) and without type 2 diabetes (blue lines, data from the SURMOUNT-1 trial) during 52–72 weeks treatment with tirzepatide 5 mg, 10 mg, or 15 mg s.c. once weekly.

Serious adverse events (SAEs) for participants treated with tirzepatide were reported with a frequency of 5–7% in participants without T2D (SURMOUNT-1) and 6–9% in participants with T2D (SURMOUNT-2 trial).26,27 The frequency of SAEs in the semaglutide 1 mg once weekly group was 3% compared with 5–7% in the tirzepatide 5–15 mg once weekly groups in the SURPASS-2 trial.29

Antibodies against tirzepatide was analyzed from 7 Phase III trials investigating pharmacokinetics, efficacy, and safety of tirzepatide in participants. In total, 51% of participants developed antidrug antibodies (no difference between 5 mg, 10 mg, or 15 mg once weekly groups) with no observed differences in terms of pharmacokinetics or efficacy in reducing HbA1C for this group compared to participants with no antidrug antibodies. Participants with antidrug antibodies had a higher frequency of injection site reactions, but these were non-serious and transient. Overall, antidrug antibodies were deemed not to have a significant impact on safety.28,30,31,34,42

## Discussion

In clinical trials tirzepatide has been demonstrated to elicit substantial weight reduction, with less weight loss in trial participants with T2D compared to participants without T2D. In the SURMOUNT-2 trial, participants with T2D achieved a mean weight loss of up to 14.7% from baseline (11.6% estimated treatment difference relative to placebo) after 72 weeks. On the other hand, in the SURMOUNT-1 trial with a similar dose-escalation and involving slightly younger and more overweight participants without T2D, a mean weight loss of up to 20.9% from baseline (17.8% difference from placebo in change in body weight) was reported after 72 weeks. The mechanisms behind this difference is unknown, but the same trend has been reported for the GLP-1 receptor agonists.43,44 The two SURMOUNT studies provide valuable comparisons since they share a similar duration and involve participant populations that are comparable, with the primary distinction being the presence or absence of T2D among participants. While full data from other SURMOUNT trials have not yet been published, a recent announcement from the manufacturer of tirzepatide (Eli Lilly and Company, Indianapolis, USA) revealed some results from the SURMOUNT-3 and −4 trials. Here, a mean weight reduction of 24.5% (placebo adjusted net weight loss) after 72 weeks of treatment with tirzepatide in obese adults with weight-related comorbidities, but without T2D, was reported for the SURMOUNT-3 trial.45 Furthermore, in the SURMOUNT-4 trial it was reported that overweight or obese participants without T2D, who remained on tirzepatide for a total of 88-weeks had a 26% reduction in bodyweight (not placebo adjusted).45 As such, the difference in efficacy of tirzepatide between individuals with T2D compared with individuals without T2D may prove to be even greater than previously reported. While higher BMI is a predictor for higher absolute weight reduction, it cannot by itself explain these large differences in percentage body weight change from baseline.46 To our knowledge, no clear explanation has been provided for the difference in weight-reducing effects of GLP-1(/GIP) receptor agonists in patients with or without T2D. However, the underlying mechanisms behind this are likely to share similarities to the reduced glucoregulatory effects of both GLP-1 and GIP observed in patients with T2D compared to age- and BMI-matched controls without T2D.47

The GLP-1 receptor mono-agonists constitute relevant efficacy comparisors in terms of weight reduction. While some SURPASS trials compared tirzepatide directly with other GLP-1 receptor mono-agonists (dulaglutide and semaglutide), these comparators were not administered in adequate doses for optimal weight-lowering effects. In the SURPASS-2 trial, semaglutide was administered at a dose of 1 mg once weekly, while doses of up to 2.4 mg once weekly are now approved for weight management therapy. In the SURPASS J-Mono trial, tirzepatide was compared to a weekly dose of 0.75 mg dulaglutide, although doses of up to 4.5 mg once weekly have been approved (and have demonstrated enhanced efficacy).13,29,33,48,49 Semaglutide in doses approved for weight management (2.4 mg semaglutide once weekly) resulted in a weight loss of 6.2% relative to placebo (treatment policy estimand) in individuals with T2D after 68 weeks in the STEP-2 trial.26,50 As such, an indirect comparison of the highest approved doses of semaglutide (2.4 mg once weekly for 68 weeks) with highest dose of tirzepatide (15 mg once weekly for 72 weeks) suggests superior weight reducing effects of tirzepatide in individuals with T2D (ie, 6.2% versus 11.6%). For individuals without T2D, semaglutide 2.4 mg once weekly resulted in a body weight reduction of 12.4% relative to placebo (treatment policy estimand) after 68 weeks (STEP-1 trial) – again lower than the 17.8% relative to placebo reported in the SURMOUNT-1 trial with tirzepatide with only 4 weeks longer treatment duration.6 Thus, the reported weight loss with tirzepatide is superior compared to the weight loss reported with other GLP-1 receptor agonists irrespective of the presence of the T2D diagnosis.

Is the suggested superiority of tirzepatide in terms of weight reduction a result of a better GLP-1 receptor agonism, or is it primarily the addition of the GIP receptor agonism that impacts body weight regulation – or is it perhaps a combination of the two? Tirzepatide activates both the GLP-1 and the GIP receptor, whereas the affinity and potency are different from that of the naturally occurring hormones. Several mechanisms involving GIP receptor agonism are proposed to play a role in weight regulation. One hypothesis describes that GIP receptor activity mitigates the internalization of the GLP-1 receptor thereby enhancing GLP-1 receptor signalling.16 Another hypothesis builds on evidence supporting that GIP receptor agonism in the central nervous system contributes to a reduced food intake and thereby a reduction in body weight. Interestingly, there are studies with contradictory findings regarding the impact of GIP receptor agonism and antagonism on the regulation of body weight.51 GIP and GLP-1 combined are responsible for approximately 60–75% of insulin secretion (the incretin effect). In healthy individuals GIP has been suggested to be the most important contributor of the two hormones, suggesting that GIP may provide important additional effects in terms of body weight reductions perhaps increasingly so in individuals without diabetes or with treatment-induced normalization of body weight and glycaemia.52 Yet another hypothesis builds on the suggested effects of GIP receptor activation to alleviate nausea induced by GLP-1.51 While high doses of semaglutide and tirzepatide have not been directly compared, the weight loss and incidence of gastrointestinal AEs for lower doses of semaglutide 1 mg and tirzepatide 5 mg were very similar when directly compared in the SURPASS-2 trial, implying that any potential impact of GIP on reducing nausea at lower doses is most likely marginal.29 Finally, it must be considered if it is simply a matter of the administered dose, something which an ongoing study evaluating the weight-loss potential of semaglutide 7.2 mg weekly will disclose.53

Safety and tolerance of tirzepatide are important, as are any potential differences in frequency or type of AEs seen in individuals with and without T2D. Comparing the SURMOUNT-1 and −2 trials (similar duration and demographics but participants with and without T2D), nausea was reported by 31% (non-T2D) vs 23% (T2D) of participants during treatment with the highest tirzepatide dose (15 mg). Following the same pattern, diarrhea was reported by 23% (non-T2D) vs 19% (T2D) of participants treated with tirzepatide 15 mg. In contrast, vomiting was reported by a similar proportion of participants in the two groups 12% (non-T2D) vs 13% (T2D) treated with tirzepatide 15 mg. Collectively, AEs in participants without T2D were reported in up to 82% of participants with 4–7% of participants discontinuing due to AEs. For participants with T2D, AEs were reported in up to 77% of with similar number (ie, 4–7%) discontinuing due to AEs. Important SAEs to consider in participants both with and without T2D are the relatively rare events of acute cholecystitis and acute pancreatitis, which did not differ between groups.

Tolerability of tirzepatide was generally improved with a longer dose-escalation period, but the frequency of participants experiencing any adverse effects remained high (77–82% in the SURMOUNT trials), and an even higher frequency of AEs among participants with T2D of up to 95% was reported in an Asian-Pacific population with a lower mean body weight in the SURPASS-AP-combo trial.35 Although the frequency of AEs is high, it is worth noting that AEs were predominantly gastrointestinal in nature and most pronounced during the dose-escalation phase. Additionally, the average duration typically spanned from 2 to 4 days.26,35 Based on the collective trial data most individuals treated with tirzepatide are bound to experience transient, gastrointestinal AEs independent of diabetes status.

Discussions on the beneficial effect of weight loss remains, and an important feature of tirzepatide (or any other weight management drug) is its capacity to lower the occurrence of other diseases, such as cardiovascular outcomes. GLP-1 receptor agonists lower the risk of heart failure hospitalization in patients without prior heart failure; however, no statistically significant reduction has been demonstrated in patients with a history of heart failure.54,55 A recently published study revealed that participants with obesity or overweight who experienced weight reduction (9.4% from baseline) after treatment with 2.4 mg semaglutide for an average of 34 months saw reductions in MACE with a hazard ratio 0.80 [95% CI: 0.72 ─ 0.90] compared to those who received placebo.56 Longer studies of tirzepatide are needed to investigate if similar results are achievable with tirzepatide (as of publication of this article, the longest duration of follow-up in a trial for treatment with tirzepatide has been 72 weeks). Some investigations have tried to examine cardiovascular outcomes, utilizing a post-hoc meta-analysis of SURPASS trials that showed non-significant decreases in HR for MACE. Future studies will investigate if there are significant, positive effects on MACE: SURPASS CVOT (cardiovascular risk assessment, [NCT04255433](https://clinicaltrials.gov/ct2/show/NCT04255433)) will finalize in 2024 and SURMOUNT-MMO (reduction in morbidity and mortality in adults with obesity, [NCT05556512](https://clinicaltrials.gov/ct2/show/NCT05556512)) will finalize in 2027. These trials will provide important results on the potential benefits of tirzepatide.

## Conclusion

Treatment with the dual GIP and GLP-1 receptor agonist tirzepatide elicited substantial weight reduction in individuals both with and without T2D, showing a higher level of efficacy compared to what has been previously documented with GLP-1 receptor mono-agonists. A notable and unexplained discrepancy, akin to what has been observed with other weight-loss medications, continues to exist in the reported weight loss between individuals with T2D compared to the considerably greater weight loss seen in individuals without T2D. Although the occurrence of AEs is relatively common with tirzepatide, these AEs were typically gastrointestinal in nature and self-resolving within a few days. Importantly, the frequency and nature of these AEs did not differ greatly between individuals with or without T2D, apart from a minor difference with participants with T2D reporting lower frequencies of nausea and diarrhea. While future studies are required to validate the effectiveness and safety of tirzepatide in a variety of populations and explore the potential for enhancements in the well-being and survival of treated patients, the reviewed data constitutes a promising prospect for tirzepatide and the future development of weight-loss medications involving agonism at multiple receptors.

## Disclosure

The author(s) report no conflicts of interest in this work.

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url: https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2024.1386542/full
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ORIGINAL RESEARCH article 

Front. Endocrinol. , 04 June 2024

Sec. Obesity 

Volume 15 - 2024 |  [ https://doi.org/10.3389/fendo.2024.1386542 ](https://doi.org/10.3389/fendo.2024.1386542)

# Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus

[![Beatriz Rodríguez Jimnez*](https://loop.frontiersin.org/images/profile/2651434/74)Beatriz Rodriguez Jimenez](https://loop.frontiersin.org/people/2651434)*[![Pablo Rodríguez de Vera Gmez](https://loop.frontiersin.org/images/profile/2413502/74)Pablo Rodriguez de Vera Gomez](https://loop.frontiersin.org/people/2413502)[![Samuel Belmonte Lomas](https://loop.frontiersin.org/images/profile/2657955/74)Samuel Belmonte Lomas](https://loop.frontiersin.org/people/2657955)![ngel Manuel Mesa Díaz](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Ángel Manuel Mesa Diaz![Irene Caballero Mateos](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Irene Caballero Mateos![Irene Galn](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Irene Galan[![Cristbal Morales Portillo](https://loop.frontiersin.org/images/profile/2658130/74)Cristobal Morales Portillo](https://loop.frontiersin.org/people/2658130)![María Asuncin Martínez-Brocca](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Maria Asuncion Martinez-Brocca

  * Servicio de Endocrinologia y Nutricion, Hospital Universitario Virgen Macarena, Seville, Spain



**Background:** Glucagon-like peptide-1 receptor-agonists (GLP-1ra), such as semaglutide, have emerged as promising treatments, demonstrating sustained weight reduction and metabolic benefits. This study aims to assess the impact of oral and subcutaneous semaglutide on body composition and metabolic parameters in patients with T2DM and obesity.

**Methods:** A 24-week quasi-experimental retrospective study including adults with T2DM and obesity (BMI ≥ 30 kg/m²) who were treated with either daily-oral or weekly-subcutaneous semaglutide. Body composition was measured using bioelectrical impedance analysis, evaluating fat mass, fat-free mass, total body water, skeletal muscle mass, and whole-body phase angle. Analytical parameters included lipid profile and glycaemic control. Statistical analyses were performed using SPSS v.26.

**Results:** Participants (n=88) experienced significant weight loss after treatment with semaglutide (9.5% in subcutaneous, 9.4% in oral, P<0.001). Weight reduction primarily resulted from fat mass reduction without substantial lean mass compromise. Visceral fat area decreased, whiles phase-angle remained stable. Improvements in lipid profiles and glycaemic control were observed, with a decrease in both HbA1c and insulin requirements. Multivariate analysis demonstrated comparable impacts of oral and subcutaneous semaglutide on body composition.

**Conclusion:** Semaglutide, administered orally or subcutaneously, demonstrated positive effects on body composition, metabolic and glycaemic control in patients with T2DM and obesity. This real-world study highlights the potential of bioelectrical impedance analysis in assessing antidiabetic drugs' impact on body composition, providing valuable insights for future research and clinical applications.

## Introduction

Treating type 2 diabetes mellitus (T2DM) with the aim of avoiding its well-known long-term complications has been a therapeutic challenge over the last century. Increasing knowledge of hormones within the incretin family, has led to the identification and development of a series of agents that expand therapeutic options when treating patients with these pathologies. In particular, glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1ra) has demonstrated sustained, clinically significant body weight reductions in patients with T2DM and obesity (1-3).

GLP-1 is a gut hormone secreted by distal enteroendocrine L-cells, located in the small bowel and colon (4). It is released in response to meal ingestion, stimulating glucose-dependent insulin secretion by pancreatic beta-cells (5). Additionally, glucagon secretion is suppressed by GLP-1 (4), leading to a glucose-dependent reduction of hepatic glucose production (5). This process is regulated by glucose levels, mitigating the risk of hypoglycaemia (6). GLP-1 receptors are widely expressed in tissues beyond the gastrointestinal tract, including the endocrine pancreas, kidneys, cardiovascular system, and various regions of the nervous system (4, 5, 7). Considering the broad expression of GLP-1 receptors throughout the body, GLP-1 serves multiple roles beyond glucose homeostasis. For instance, gastric emptying rate is decelerated in response to glucose increase. Modulation of satiety is also mediated by GLP-1 (8), as well as regulation of energy intake via hypothalamic feeding circuits (9, 10).

GLP-1ra mimic native GLP-1's pancreatic actions, stimulating weight loss and improving glycaemic control (5), as well as promoting physiological effects such as cardiovascular risk reduction (5, 11, 12), atherogenesis prevention through vascular inflammation modulation (13, 14) and renoprotective and neuroprotective effects (15-18), which enhance GLP-1ra's beneficial outcomes. This provides medical professionals a promising tool to treat patients living with obesity and T2DM, beyond insulin and prior diabetic management approaches. However, GLP-1 based treatments can also entail adverse effects, which are mainly gastrointestinal, notably nausea, vomiting, and diarrhoea (19). Such effects usually decrease over time with continued therapy and can be mitigated by adjusting the dosage (20).

Semaglutide is a GLP1-ra, with 94% amino acid sequence homology with native GLP-1 (21). Structural modifications of the molecule have enabled semaglutide to be less susceptible to degradation by dipeptidyl peptidase-4, thus extending its half-life to nearly a week (22). It is already known that semaglutide achieves reduction in body weight which in turn improves glycaemic control and thus reduces risk associated with poorly controlled T2DM (23), but it is still necessary to expand the information regarding its effect on body composition, which is why we performed this investigation.

Bioelectrical impedance (BIA) represents a non-invasive, relatively fast and simple tool to estimate body composition, providing information beyond body mass index (BMI) and other anthropometric measurements.

Within this study, we aim to assess the impact of GLP-1ra Semaglutide on body composition of patients with T2DM and obesity, as a reflection of their nutritional status, while evaluating possible metabolic changes after a 24-week period of treatment.

## Materials and methods

### Design and subjects

We conducted a 24-week follow-up quasi-experimental retrospective study to assess changes in body composition and the effect of semaglutide on analytical parameters. Recruitment was carried out systematically and consecutively in the Endocrinology and Nutrition Department of our hospital, the Virgen Macarena University Hospital in Seville, during the years 2020-2022.

Adults (18 years or older) with T2DM, insufficient glycaemic control [glycated haemoglobin (HbA1c) ≥ 7%] and Obesity (BMI ≥30kg/m2) who underwent treatment with GLP1-ra, both in its subcutaneous and oral forms, were included in our study. Those who were already taking GLP1-ra or had in the past, subjects with a follow-up period shorter than 12 months and those who had to interrupt treatment due to adverse events or drug intolerance (predominantly gastrointestinal symptoms), were excluded from the study.

Subjects were divided into 2 groups depending on the intended route of Semaglutide administration they were to receive: daily oral semaglutide (OS) or weekly subcutaneous semaglutide (SS). Due to significant differences in their baseline characteristics, both groups were independently analysed within the context of the study, which was conducted under real-life conditions (see Tables 1, 2, where differences in baseline characteristics between treatment groups are shown with *).

Table 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t001.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t001.jpg)

**Table 1** Baseline characteristics of the sample divided into treatment groups.

Table 2

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t002.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t002.jpg)

**Table 2** Variation in body composition parameters from baseline to end of follow-up (6 months) using bioelectrical impedance analysis.

To ensure intervention homogeneity, we included patients who, based on their tolerance, adhered to the subsequent therapeutic regimen: following a 4-week dose escalation, medication was administered with a starting dose of 0.25mg once weekly, followed by 0.5mg weekly and finally 1 mg maintenance dose in SS; the initial dosage in the OS group was 3 mg taken daily for 4 weeks, followed by an additional 4 weeks at 7mg, and finally maintenance dose of oral semaglutide, 14 mg. Participants who were unable to adhere to this therapeutic protocol due to intolerance, adverse effects, or poor treatment compliance were excluded from the study (Figure 1). The remaining concomitant treatment (including hypoglycemic and hypolipidemic treatment) was indicated according to standard clinical practice guidelines.

Figure 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-g001.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-g001.jpg)

**Figure 1** Study design-dose range administration. In order to obtain comparable data, only patients who followed a monthly dose escalation as represented by d and h, were selected. In brackets are the number of patients who followed each treatment scheme. SS, subcutaneous semaglutide; OS, oral semaglutide; mg, milligrams; M, months.

Participants who experienced adverse effects or drug intolerance (mainly gastrointestinal symptoms including nausea, diarrhoea, and abdominal discomfort), rendering them unable to complete the prescribed treatment regimen, were excluded from bioimpedance analysis and subsequently not included in our study.

### Educational intervention

Patients were given general advice for incorporating physical activity and adopting a healthy lifestyle, based on the Mediterranean diet and active living to discourage sedentary behaviour. These guidelines were initially conveyed during the first visit and further emphasized by our nursing team in a brief 15-minute session, in which patients were instructed on the administration of semaglutide. Regarding dietary habits, patients received recommendations advocating for the consumption of fruits and vegetables, minimally processed foods, legumes, fish, and whole grains, along with hydration based on water over soft drinks and alcohol. Additionally, general physical activity guidelines were provided, encouraging an active lifestyle, avoiding sedentary behaviour, and recommending 30-60 minutes of daily aerobic exercise and 2-3 days per week of strength training, adapted to individual physical capabilities. This educational intervention was carried out as part of daily clinical practice, not with the aim of evaluating its impact.

### BIA measurement and analytical parameters

Body composition was measured using multi-frequency BIA (MF-BIA) (Inbody 770, Inbody Co., Ltd., Korea). All measurements were performed in the morning, at baseline and at the end of follow-up. Parameters including fat mass (FM), fat free mass (FFM), total body water, skeletal muscle mass and phase angle (PhA) where registered.

Blood tests were performed after 8 to 10 hours of fasting; samples were collected to measure analytical parameters such as haemoglobin, platelet count, fasting plasma glucose and HbA1c, creatinine, total cholesterol, and its lipoproteins.

### Study endpoints and assessments

The main study variable was reduction in body FM from baseline to week 24 of semaglutide treatment. Secondary efficacy end points at week 24 included changes in body composition, such as body water, skeletal muscle, and PhA; as well as modifications in analytical parameters; particularly lipid profile and glycaemic control.

### Statistical analysis

We estimated the required sample size to be 60 participants (30 for oral and 30 for subcutaneous semaglutide), assuming a two-sided hypothesis test with a 95% confidence level and accounting for a potential 10% loss. This estimation was based on a minimum clinically relevant difference of -10% in fat body mass at the conclusion of the follow-up (22, 23).

Categorical variables were expressed in numbers and percentages. Continuous variables were expressed as mean and standard deviation (SD) for normal distributions or median and interquartile range (IQ) if distributions were skewed. We used t-student test and Wilcoxon test for the comparison of continuous variables, normally distributed and nonnormally distributed respectively. Normality of quantitative data was tested using the Kolmogorov-Smirnov test. Homoscedasticity was evaluated using Levene´s test.

We conducted a multivariate analysis using multiple linear regression to adjust for predictor variables of FM loss percentage (dependent variable). Independent variables were selected from those that exhibited a significance level of p < 0.15 in the univariate analysis (data not shown) and those where significant differences were observed between treatment groups. The final number of included variables was determined based on the criteria of greater parsimony and better discrimination capacity, with reference to an area under the curve (AUC) >0.75 in the ROC curve analysis. The model's goodness of fit was assessed using Hosmer-Lemeshow's test.

The statistical significance was set at p < 0.05 (two-tailed hypothesis testing). The strength of association was presented as a mean difference and 95% confidence interval (CI).

Statistical analyses were performed using the SPSS v.26/PC software package (IBM Statistics).

### Ethics statement

Written informed consent was obtained from all subjects. This study was conducted in accordance with the Helsinki Declaration of 1975, as revised in 2008; and was approved by the Research Ethics Committee of the Hospital Universitario Virgen Macarena of Seville.

## Results

### Patients, baseline characteristics

A total of 203 patients were initially identified as potential candidates to participate in this study, of whom 88 were selected; 55 patients in the SS wing and 33 patients who received OS.

The mean age in the SS group was 55.3 ± 10.4 years, of which 47.3% were women, and had a mean BMI of 40.1 ± 11 kg/m2. In the OS group, mean age was 61.8 ± 7 years, 33.3% women and BMI 34.2 ± 3.9kg/m2. Disease duration was 7.2 ± 6.3 years for SS and 9.6 ± 6.3 years for OS.

Regarding the hypoglycaemic treatment our patients had been taking prior to the introduction of Semaglutide; a total of 64 patients were taking metformin [39 (70.9%) in the SS group and 25 (75.8%) in the OS group], and basal insulin was part of the glucose-lowering treatment of 41 subjects [24 (43.69%) in the SS group and 17 (51.5%) in the OS group]. Their clinical characteristics, comorbidities, and treatment they were receiving prior to the introduction of Semaglutide are listed in Table 1.

### Impact of semaglutide in body composition parameters

Throughout follow-up, participants experimented a significant reduction of their weight, 9.5 ± 5.7% with SS and 9.4 ± 5.9% with OS. We observed that weight loss was at the expense of reducing FM percentage [-4% (IC 95% [-4.9; -3.1], p< 0.001) in SS and -5.2% (IC 95%[-6.7; -3.6], p< 0.001) in OS] while increasing the percentage of FFM [3.6% (IC 95% [2.8; 4.6], p< 0.001) in SS and 5.2% (IC 95%[3.6; 6.7], p< 0.001) in OS] (Figure 2).

Figure 2

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-g002.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-g002.jpg)

**Figure 2** Changes in the composition parameters from baseline to end of follow-up.

Considering weight reduction in absolute numbers, in the SS group, loss of FM was -8.5 kg (95% CI [-10.2; -6.9], p < 0.001), while the reduction in lean mass was -1.7 kg (95% CI [-2.4; -1], p < 0.001). These results were consistent in the OS group, where the loss of FM was -8 kg (95% CI [-9.7; -6.2], p < 0.001), and that of lean mass -0.7 kg (95% CI [-1.5; 0.2], p = 0.112).

Nevertheless, PhA remained constant on average during follow-up [-0.03° (CI 95% [-0.1; 0.1], p = 0.529) in SS and -0.1° (CI 95% [-0.2; 0], p = 0.068) in OS].

Changes in other body composition parameters were also seen, such as a decrease in total body water and visceral fat area (VFA), which was -30.2cm2 (CI 95% [-37.5; -23.2], p <0.001) in SS and -42.3 cm2 (CI 95% [-52.9; -31.8], p <0.001) in OS. Table 2 complies information regarding these changes.

### Effect on analytical and clinical parameters

In addition to the benefit observed on patients' body composition, their laboratory metrics also improved during the follow-up period. For instance, lipid profile demonstrated positive changes with a reduction in total cholesterol of -30mg/dl (CI 95% [-44.5; -17.5], p < 0.001) in SS and -49.4mg/dl (CI 95% [-70; -28.8], p < 0.001) in OS (Table 3). At the same time, metabolic control was optimized with a reduction in HbA1c -3.8% (CI 95% [-4.5; -3], p < 0.001) in SS and -3% (CI 95% [-3.7; -2.2], p < 0.001) in OS; achieving optimal metabolic control (HbA1c <7%) in 92.3% of patients undergoing treatment with SS and 75.8% in those who received OS. In both groups, we observed a decrease in insulin requirements after 6 months, with statistical significance noted in the SS group, where patients required 4 UI (IC 95% (-9, 0), p =0.01) less.

Table 3

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t003.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t003.jpg)

**Table 3** Changes in analytical parameters from baseline to end of follow-up (6 months).

### Multivariate analysis

Additionally, we performed a multivariate analysis using multiple linear regression, with the percentage of mass loss at the end of follow-up as the dependent variable for all study participants (n=88). As independent variables, we included the administration route of semaglutide, along with those variables where significant differences were identified at baseline. We observed that percentage of FM lost at the end of follow-up was determined by the initial percentage of FM, baseline BMI and concomitant treatment with iSGLT2 (sodium-glucose linked transporter inhibitors) and insulin. Notably, no significant association was observed with the treatment administration route (Table 4).

Table 4

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t004.jpg) ](https://www.frontiersin.org/files/Articles/1386542/fendo-15-1386542-HTML/image_m/fendo-15-1386542-t004.jpg)

**Table 4** Multivariate analysis using multiple linear regression to adjust for predictor variables of fat mass loss percentage.

## Discussion

T2DM is a highly prevalent disease accounting for nearly 95% of all diabetes (24), with a rapidly increasing prevalence. Noticeably, a substantial proportion of individuals with T2DM remain unaware of their diagnosis, leading to lost opportunities in early management. Meanwhile, the global prevalence of obesity has almost tripled since 1975 according to the World Health Organization. We conducted a study that examines the changes observed in an adult population with T2DM and obesity, focusing on modifications in body composition evaluated through MF-BIA.

Assessing body composition is valuable for individual evaluation and estimating changes over time. Beyond anthropometry, MF-BIA provides insights into various body components and their interrelations in a given person (25). Other methods used to study body composition include dual-energy x-ray absorptiometry (DXA) and magnetic resonance imaging (MRI) among others. DXA offers accurate measurements of various body components in addition to bone mineral density data. Conducted with standardized protocols, these measurements ensure consistency and comparability across diverse studies and populations. Several studies have indicated comparable outcomes between DXA and MF-BIA (26-29). For instance, Schoenfeld et al. found no significant differences in mean changes between MF-BIA and DXA scans for FM, percent body fat, and FFM (30). Similarly, other investigations comparing MF-BIA with DXA in body composition evaluation reported similar findings for total body and segmental soft tissue measures (31). Likewise, MRI's precision allows detailed visualization of various tissues, aiding accurate assessment of fat distribution, muscle mass, and other components. MRI's whole-body imaging capability enables comprehensive evaluation of adipose tissue and lean mass distribution, offering valuable insights into overall health. It is non-invasive, ensuring patient safety with high-resolution images and no ionizing radiation. MRI's quantitative analysis allows precise measurements of tissue volumes and densities, facilitating quantitative assessments of fat content and distribution. This makes it valuable for diagnosing and monitoring conditions like obesity, sarcopenia, and metabolic disorders. Its wide acceptance among patients and versatility in research further highlight MRI's significance for assessing body composition and guiding clinical decisions in medical settings (32).

In contrast, BIA offers several advantages for assessing body composition in medical practice. Its non-invasive nature ensures patient comfort and safety, being suitable for individuals of different ages and health conditions. BIA devices are portable, affordable, and easy to use, making them accessible in various healthcare settings. The rapidity of BIA assessments allows for efficient incorporation into clinical practice, providing quick insights into body composition without significant time investment. Additionally, BIA's versatility permits detailed assessments of both total and segmental body composition, offering valuable information on fat and lean mass distribution. Longitudinal monitoring capabilities enable clinicians to track changes in body composition over time, aiding in the management of conditions such as obesity or muscle wasting disorders (25).

BIA estimates body composition based on a series of predictive equations developed for a specific population. Alongside data on the different body compartments, BIA provides raw electrical values: impedance, resistance, reactance and PhA (the arctangent of the ratio of reactance to resistance (33)). BIA calculates secondary data on fluid compartments, such as total body water, intracellular water, and extracellular water. From these, fat-related compartments (FM and FFM) are derived, as the body's water content primarily resides in FFM (34). Consequently, achieving optimal outcomes for entire body compartments, even in individuals with good health, relies on choosing a suitable equation (35). Regardless of its inherent limitations as an indirect method, BIA continues to be extensively used in both epidemiological studies and individual assessments.

Regarding body composition, while the baseline characteristic of the groups differed, our multivariate model revealed a similar impact of oral versus subcutaneous semaglutide on weight loss. This suggests that there may not be significant differences between the two administration forms. Nonetheless, it is crucial to conduct studies with a specific design to thoroughly evaluate this hypothesis. Our cohort experimented a reduction in their body weight of -10kg (-9.5%) and -8.6kg (-9.4%) depending on semaglutide's route of administration (SS and OS respectively), slightly higher than that described in literature (23). Weight reductions ranging from 5-10% are considered clinically significant and correlate with cardiovascular risk improvement (36). We observed that weight loss was to a greater extent due to a reduction in the percentage of FM than the percentage of FFM, suggesting a decrease of FM without significant losses in the lean mass component.

There has been ongoing discourse in the literature regarding a potential association between Semaglutide use and the onset of sarcopenia. However, most studies indicate that Semaglutide primarily induces weight loss by reducing FM while either preserving muscle mass or even enhancing the relative proportion of skeletal muscle, with minimal or non-clinically relevant impact on muscle strength (37-40). In our cohort, we observed that the loss of muscle tissue was not significant in the OS group. Conversely, in the SS group, there was a statistically significant reduction in muscle tissue, which could be attributed to the greater overall weight loss compared to the OS group. Given that individuals starting the SS option had, on average, a higher BMI and thus a greater degree of obesity, they also began with a higher baseline lean mass compared to those in the OS group, which could explain why they experienced a proportionally greater decrease in their lean mass component. The Skeletal Muscle Index (kg/m2) decreased in both groups, with significant reductions in absolute values observed only in the SS group. These findings underscore the apparent predominantly positive impact of semaglutide on fat mass reduction. However, considering our results and previous research (20), it would seem highly advisable to implement targeted physical exercise to preserve and potentially enhance muscle mass in patients receiving GLP-1 based therapies.

Traditionally, the association between BMI and long-term all-cause mortality was described as a U-shape (41), as a result of different underlying risk functions of opposite directions associated with fat and fat-free body compartments (42). Recent investigation has shown an inverse association between FFM and mortality, whereas FM was directly associated with mortality (43). A clinical study including a series of patients with BIA assessment before and after follow-up, showed increased mortality by weight loss probably attributed to loss in FFM (44). Likewise, another study suggested that the increase in mortality seen in their population was less in subjects who alongside with their weight loss has a relatively high physical activity (45). This highlights how detrimental the FM component is and points out the need to consider it in clinical practice, emphasising that relying solely on BMI could be insufficient when evaluating a patient's metabolic state.

Our cohort underwent a reduction in VFA after treatment with semaglutide both in SS and OS routes of administration. VFA plays a key role in metabolic and cardiovascular disease. Visceral adipose tissue secretes inflammatory mediators leading to a chronic low grade inflammation state (46, 47), which induces a constellation of metabolic abnormalities and diseases (46). Adiposity is an independent risk factor for glycometabolism disorder, since fat accumulation affects insulin's action by different mechanisms including insulin resistance in organs such as the liver and muscle tissue (46, 48). Over the years, evidence has suggested that the risk of adiposity-induced metabolic dysfunction is not solely determined by the quantity of accumulated fat in the body, but rather by its distribution. According to Klein et al., decreasing body FM by inducing a negative energy balance could normalize obesity-induced dysfunction.

Focusing on PhA, throughout follow-up it maintained similar values as those registered in the first body composition analysis. From these results we can infer that Semaglutide did not affect cellular integrity to a significant extent. PhA acts as a marker of the amount of electrical charge that a cell membrane can hold, related to membrane integrity, permeability, overall size and hydration (35); therefore, indicating cellular health and function (49). PhA is a raw bioelectrical parameter with a demonstrated prognostic utility (50). Its value is influenced by various factors: aging contributes to a decline on PhA as muscle mass decreases, men typically exhibit higher PhA values than women owing to greater muscle mass, and there is a positive correlation between BMI and PhA, with higher BMI values corresponding to increased PhA values. Several studies have demonstrated lower values of PhA in T2DM, relating smaller values with catabolism and longer disease duration (49). The main challenge of using PhA in clinical evaluation is the lack of consensus on cut-points and reference values. Several investigations have been carried out around the world, based on large population samples in Germany (51), the United States (52) and Switzerland (53), obtaining notable differences (35). Therefore, further research is required to establish, through standardized measurement techniques, reference cut-off points (54).

With respect to analytical parameters, glycaemic control improved significantly as proven by HbA1c and fasting plasma glucose. Clinical trials have reported reductions in the HbA1c level to be as high as 1.8%, depending on dosage and follow-up duration (23). This percentage is lower than our findings, which could correspond to higher HbA1c levels at baseline in our cohort compared to clinical trials, where inclusion criteria are more stringent, since our study was conducted in a real-life clinical practice setting. Attaining desired blood glucose levels is a key objective in diabetes management, since optimal glycaemic control reduces the risk of both microvascular and macrovascular complications (36, 55). In this regard, as part of everyday clinical practice, an educational activity aimed at reinforcing healthy lifestyle habits was carried out simultaneously with the treatment, which could have influenced a better weight response and glycaemic control. This protocol is standard within our endocrinology service and is routinely practiced, both within the scope of this study and as part of routine clinical care. Therefore, no assessment of its impact was conducted. GLP-1ra enhance glycaemic control by stimulating insulin secretion and by a glucose-dependent inhibition of glucagon release (56), resulting in effective glucose lowering without increased risk of hypoglycaemia (57). Consistent with this knowledge, glycaemic improvement in our cohort was not accompanied by more frequent hypoglycaemic events.

Additionally, basal insulin requirements in our cohort decreased after follow-up, highlighting the fact that our patients were metabolically in better conditions after semaglutide treatment. This is a promising finding, since insulin, although effective in hyperglycaemic control for many patients, is associated with hypoglycaemia and weight gain (57).

Lipid profile showed improvement as well, with significant reductions in total-cholesterol and non-significant reduction in Low-density lipoprotein cholesterol concentrations. This is consistent with SUSTAIN 9's trial, where both parameters significantly decreased in the same proportion (58). It is suggested that such improvement could come alongside with reductions in body weight and glucose levels; GLP-1ra have also been shown to regulate cholesterol and triglyceride concentrations via several different pathways (59).

Recently, two studies similar to ours have been published, yet with certain differences. Both studies investigated changes in body composition after 26 weeks of treatment with semaglutide. One study (60), assessed the impact of OS in 32 patients with a mean BMI of 28.2 kg/m2. Results showed a weight loss of 4 kg at 6 months, accompanied by improvements in lipid profiles and a significant reduction in HbA1c at 3 and 6 months of follow-up. In the other study (37), involving subcutaneous administration of semaglutide in a population of 40 patients with a mean BMI of 38.8 kg/m2, a weight loss of 9.89kg was observed after 6 months. This second study showed a weight loss pattern consistent with our findings, probably influenced by a similar baseline BMI between the two studies. It is noteworthy that both studies established as an exclusion criterion the concomitant use of other hypoglycaemic agents such as iSGLT2 inhibitors. Additionally, not all patients reached full semaglutide dose: in the SS study, only 5% reached a weekly dose of 1 mg; in the OS study, all patients remained on an intermediate (7 mg) or initial dose (3 mg). In other words, the patients did not uniformly receive the same treatment regimen. Furthermore, sample size in both studies was limited.

Previous investigations have delved into the impact of combining physical activity programs with nutritional recommendations to aid weight reduction. It is widely recognized that structured lifestyle interventions play a pivotal role in facilitating weight loss among individuals grappling with obesity (61). Such interventions can yield significant outcomes, with a 3-5% reduction in body weight achievable through health behavioural changes, leading to tangible improvements in obesity-related comorbidities (62). Notably, Wilding et al. highlighted that combining Semaglutide treatment with lifestyle interventions effectively sustained clinically relevant weight loss in overweight or obese adults (1). In our study, patients were provided with general recommendations for adopting a healthy lifestyle and engaging in physical exercise, cantered around the Mediterranean diet and active living to deter sedentary behaviour. These guidelines were initially communicated during the first visit and subsequently reinforced by our nursing team during a brief 15-minute session. While this information was uniformly disseminated to all participants, there was no subsequent follow-up or utilization of specific programs for reinforcement.

## Limitations

We acknowledge some limitations in our study. We did not investigate a control group with which to compare the effects of the treatment on the different studied parameters. The duration of the study was limited; longer-term data would have provided more information and potentially greater modifications in body composition as well as analytical parameters. Another limitation was narrow sample size, which although proved to be statistically adequate, did not allow for a more in-depth analysis of the studied variables. Furthermore, the retrospective nature of the study represents a weakness, as well as not being able to compare our treatment groups due to the basal differences observed between them. Additionally, BIA is not considered the gold standard method, and we recognize that incorporating other body composition tests may be necessary in future research.

On the other hand, it is clearly a strength that body composition parameters were estimated from BIA rather than anthropometric predictions. Likewise, it is an advantage that our data was recorded on a real-life basis. This enhances the generalizability of our findings, given that real-world studies include a more diverse and representative patient population compared to clinical trials. Consequently, our results hold greater applicability across a broader range of individuals. Additionally, such studies directly influence clinical practice, guiding healthcare providers in making evidence-based decisions in their daily patient care.

## Conclusion

In light of these results, we conclude that semaglutide improves body composition parameters with significant losses of body FM with a lesser compromise of lean mass, as well as positively influencing glycaemic control and metabolic status. The potential for muscle mass decline exists; therefore, it should be anticipated and addressed through regular physical activity to mitigate it, considering that although this decrease is expected to be less pronounced than that of fat mass, it remains likely to occur. Integrating BIA into clinical practice enables the evaluation of antidiabetic drugs' impact on the human body from a new perspective, paving the way for upcoming studies.

## Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

## Ethics statement

The studies involving humans were approved by Research Ethics Committee of the Hospital Universitario Virgen Macarena of Seville. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study.

## Author contributions

BJ: Writing - review & editing, Writing - original draft, Visualization, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. PG: Writing - review & editing, Writing - original draft, Visualization, Validation, Supervision, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization. SL: Writing - original draft, Data curation. ÁD: Writing - original draft, Data curation. IM: Writing - original draft, Investigation, Data curation. IG: Writing - original draft, Investigation, Data curation. CP: Writing - review & editing, Resources, Investigation, Conceptualization. MM-B: Writing - review & editing, Visualization, Supervision, Project administration.

## Funding

The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: obesity, type 2 diabetes mellitus, body composition, phase angle, fat mass, lean body mass, visceral fat area, HbA1c

Citation: Rodriguez Jimenez B, Rodriguez de Vera Gomez P, Belmonte Lomas S, Mesa Diaz ÁM, Caballero Mateos I, Galan I, Morales Portillo C and Martinez-Brocca MA (2024) Transforming body composition with semaglutide in adults with obesity and type 2 diabetes mellitus. _Front. Endocrinol._ 15:1386542. doi: 10.3389/fendo.2024.1386542

Received: 15 February 2024; Accepted: 21 May 2024;  
Published: 04 June 2024.

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Copyright (C) 2024 Rodriguez Jimenez, Rodriguez de Vera Gomez, Belmonte Lomas, Mesa Diaz, Caballero Mateos, Galan, Morales Portillo and Martinez-Brocca. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Beatriz Rodriguez Jimenez, YmVhdHJpei5yb2RyaWd1ZXouai5zc3BhQGp1bnRhZGVhbmRhbHVjaWEuZXM=

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Table of contents

  * Abstract
  * Introduction
  * Materials and methods
  * Results
  * Discussion
  * Limitations
  * Conclusion
  * Data availability statement
  * Ethics statement
  * Author contributions
  * Funding
  * Conflict of interest
  * Publisher's note
  * References



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