06-10-18H20-FELIPE-DONATTO

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<p>MÚSCULOS:</p><p>Muito mais que estética</p><p>PIRACICABA - SP UNIMEP</p><p>JUDÔ Graduação</p><p>Mestrado</p><p>EISSN 1676-5133doi:10.3900/fpj.5.6.348.p</p><p>Artigo Original</p><p>Copyright© 2006 por Colégio Brasileiro de Atividade Física Saúde e Esporte.</p><p>Endereço para correspondência:</p><p>Data de Recebimento: Data de Aprovação:</p><p>348 Nov/Dez 2006Fit Perf J Rio de Janeiro v. 5 nº6 348-353</p><p>Papel Da Interleucina-6 Como Um Sinalizador Em Diferentes Tecidos</p><p>Durante O Exercício Físico</p><p>Interleucina</p><p>Resumo - O grande desafio dos fisiologistas do exercício tem sido determinar como os músculos sinalizam para o sistema nervoso</p><p>central e para os órgãos periféricos durante o exercício físico. A busca pelo conhecimento em torno dos sinalizadores produzidos</p><p>durante o exercício, as relações entre músculo, cérebro e os outros tecidos aumentou consideravelmente. A interleucina-6 (IL-6) e</p><p>outras citocinas, que são produzidas e liberadas pelo músculo esquelético, podem exercer seus efeitos no tecido adiposo, cérebro,</p><p>sistema cardiovascular e fígado, sendo denominadas de miocinas. Adicionalmente, o próprio tecido adiposo, bem como o cérebro,</p><p>pode produzir IL-6, que possivelmente atua como um sinalizador entre estes tecidos, podendo influenciar o sistema metabólico e</p><p>a fadiga durante o exercício.</p><p>Rua Major José Inácio, 2400 apt 13 Edifício Ouro Preto - Centro CEP 13560-161 São Carlos/SP</p><p>Jonato Prestes - CREF 007176-G/PR</p><p>Programa de Pós-graduação em Ciências Fisiológicas</p><p>Laboratório de Fisiologia do Exercício</p><p>Universidade Federal de São Carlos</p><p>jonatop@gmail.com</p><p>Felipe F. Donatto - CRN 18-215/SP</p><p>Núcleo de Performance Humana</p><p>Mestrado em Educação Física</p><p>Faculdade de Ciências da Saúde, Universidade Metodista de Piracicaba/SP</p><p>fdonato@ig.com.br</p><p>Rodrigo Dias</p><p>Núcleo de Performance Humana</p><p>Mestrado em Educação Física</p><p>Faculdade de Ciências da Saúde, Universidade Metodista de Piracicaba/SP</p><p>Anelena B. Frollini</p><p>Núcleo de Performance Humana</p><p>Mestrado em Educação Física</p><p>Faculdade de Ciências da Saúde, Universidade Metodista de Piracicaba/SP</p><p>Claudia Regina Cavaglieri - CRF 11-992/SP</p><p>Núcleo de Performance Humana</p><p>Mestrado em Educação Física</p><p>Faculdade de Ciências da Saúde, Universidade Metodista de Piracicaba/SP</p><p>PRESTES, J.; DONATTO, F.F.; DIAS, R.; FROLINNI, A.B.; CAVAGLIERI, C.R. Papel da Interleucina-6 como um sinalizador em diferentes</p><p>tecidos durante o exercício físico. Fitness & Performance Journal, v.5, nº 6, p. 348-353, 2006.</p><p>Outubro / 2006 Outubro / 2006</p><p>Palavras-chave: Interleucina-6, músculo esquelético, exercício, tecido adiposo, cérebro</p><p>TIPOS DE MÚSCULOS</p><p>Característica Tipo I Tipo IIa Tipo IIx</p><p>Inervação Pequena Grande Grande</p><p>Frequência de Ativação Baixa Alta Alta</p><p>Velocidade de Contração Lenta Veloz Veloz</p><p>Metabolismo Oxidativo Oxid / Glic Glicolítico</p><p>[Mioglobina] Alta Intermed. Baixa</p><p>Densidade Mitocondrial Alta Intermed. Baixa</p><p>Atividade antioxidante Alta Intermed. Baixa</p><p>Fatigabilidade Baixa Intermed. Alta</p><p>Hipertrofiabilidade Baixa Intermed. Alta</p><p>TREINAMENTO DE FORÇATECIDO MUSCULAR</p><p>ANTES DO TRENO</p><p>TECIDO MUSCULAR</p><p>DEPOIS DO TRENO</p><p>TECIDO MUSCULAR</p><p>ANTES DO TRENO</p><p>ESTIMULO DAS VIAS DE SÍNTESE</p><p>PROTEICA PÓS-TREINO</p><p>Resistance exercise modulates lipid plasma profile and cytokine content</p><p>in the adipose tissue of tumour-bearing rats</p><p>F.F. Donatto, R.X. Neves, F.O. Rosa, R.G. Camargo, H. Ribeiro, E.M. Matos-Neto, M. Seelaender ⇑</p><p>Cancer Metabolism Research Group, Institute of Biomedical Sciences, University of São Paulo, Brazil</p><p>a r t i c l e i n f o</p><p>Article history:</p><p>Received 29 February 2012</p><p>Received in revised form 8 September 2012</p><p>Accepted 14 October 2012</p><p>Available online 22 November 2012</p><p>Keywords:</p><p>Resistance training</p><p>Adipose tissue</p><p>Cancer</p><p>Cytokines</p><p>a b s t r a c t</p><p>Cancer cachexia is a multifactorial syndrome characterised by progressive weight loss, frequently accom-</p><p>panied by anorexia, sarcopenia, and chronic systemic inflammation. The white adipose tissue is markedly</p><p>affected by cachexia and contributes to this syndrome throught the secretion of pro-inflammatory factors</p><p>which reach the adjacent tissues and the circulation. A nonpharmacologic intervention that may attenu-</p><p>ate cancer cachexia is chronic physical activity, but the effect of resistance training upon adipose tissue</p><p>inflammation in cachexia has never been examined. For that purpose we designed a protocol in which</p><p>animals were randomly assigned to a control group (CT, n = 7), a Tumour bearing group (TB, n = 7), a</p><p>Resistance Trained group (RT, n = 7) and a Resistance Trained tumour bearing group (RTTB, n = 7). Trained</p><p>rats climbed a vertical ladder with an extra load attached to the tail, representing 75–90% of total body</p><p>mass, 3 times per week, for 8 weeks. In the 6th week of resistance training, tumour cells (3 ! 107 Walker</p><p>256 carcinosarcoma) were inoculated in the tumour groups. Body, adipose tissue, muscle and tumour</p><p>mass was determined, as well a blood biochemical parameters, and the hormone and cytokine profile</p><p>assessed. The glycogen content of the liver and muscle was measured. IL-10, IL-6 and TNF-a protein</p><p>expression was evaluated in the mesenteric adipose tissue (MEAT) examined. Resistance training</p><p>increased by 9% body weight gain in RTTB (final weight 310.8 ± 9.8 g), when compared with TB (final</p><p>weight 288.3 ± 4.9 g). LDL-c levels were decreased in RTTB (0.28 ± 0.9 mmol/L) by 43% when compared</p><p>with TB (0.57 ± 0.1 mmol/L). HDL-c levels were increased in RTTB (1.31 ± 0.12 mmol/L) by 15% in regard</p><p>to CT (1.13 ± 0.7 mmol/L) and 22% as compared with TB (1.07 ± 0.07 mmol/L). RTTB testosterone levels</p><p>(577 ± 131 ng/mL) were 55% higher when compared with CT (254 ± 41.3 ng/mL) and 63% higher when</p><p>compared with TB (221 ± 23.1 ng/mL). Adiponectin levels were augmented in RT (23 lg/mL) by 43%</p><p>when compared with TB (11 lg/mL). Protein expression of IL-6 was increased 38% in TB MEAT</p><p>(5.95 pg/lg), as compared with CT (3.64 pg/lg) and 50% compared with RTTB (2.91 pg/lg). Similar</p><p>results with respect to TNF-a TB (7.18 pg/lg) were observed: 39% and 46%, higher protein expression</p><p>in comparison with CT (4.63 pg/lg) and RTTB (3.8 pg/lg), respectively. IL-10 protein expression was</p><p>found to be increased in TB (4.4 pg/lg) and RTTB (3.2 pg/lg) 50% and 47%, respectively, in comparison</p><p>with CT (1.2 pu/lg). The IL-10/TNF-a ratio was higher in RTTB in relation to all others experimental</p><p>groups. The results show a robust effect of resistance exercise training in preventing important symp-</p><p>toms of cancer cachexia, thus strongly suggesting it may appear as an alternative to endurance exercise</p><p>as a non-pharmacological therapy in the management of this syndrome.</p><p>Crown Copyright ! 2012 Published by Elsevier Ltd. All rights reserved.</p><p>1. Background</p><p>Cachexia is a multifactorial syndrome characterised by progres-</p><p>sive weight loss, frequently accompanied by anorexia, sarcopenia,</p><p>and chronic systemic inflammation [1]. It is today envisaged as a</p><p>degenerative chronic inflammatory disease, being deeply related</p><p>with the increase of pro-inflammatory factors, especially tumour</p><p>necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) [2]. We have</p><p>previously shown [3] than in addition to presenting morphological,</p><p>biochemical and physiological alterations in response to cachexia,</p><p>the white adipose tissue may function as an important contributor</p><p>to cachexia-related inflammation, as it actively secretes</p><p>pro-inflammatory factors which reach the adjacent tissues and</p><p>the circulation [4].</p><p>To the present day, no specific interventions have proven effec-</p><p>tive in preventing or reversing cachexia. Interventions such as</p><p>nutritional supplementation and appetite stimulants are only</p><p>partially helpful. On the other hand, a most promising nonpharma-</p><p>cological intervention that may attenuate cancer cachexia is</p><p>chronic physical activity [5]. The literature shows benefits that</p><p>range from improvement of overall physical function, to reduce fa-</p><p>tigue, and augment of life quality [6], and attenuation of the side</p><p>1043-4666/$ - see front matter Crown Copyright ! 2012 Published by Elsevier Ltd. All rights reserved.</p><p>1 Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Ave. Morones Prieto 3000,</p><p>Monterrey N.L. 64710, Mexico; amgonzalezgil@hotmail.com</p><p>2 Tecnologico de Monterrey, Center for Research in Clinical Nutrition and Obesity, Ave. Morones Prieto 300,</p><p>Monterrey N.L. 64710, Mexico</p><p>3 Tecnologico de Monterrey, Cardiovascular and Metabolomics Research Group, Hospital Zambrano Hellion,</p><p>San Pedro Garza Garcia P.C. 66278, Mexico</p><p>* Correspondence: lelizond@tec.mx</p><p>Received: 26 May 2020; Accepted: 18 June 2020; Published: 26 June 2020</p><p>!"#!$%&'(!</p><p>!"#$%&'</p><p>Abstract: Exercise is an e↵ective strategy for preventing and treating obesity and its related</p><p>cardiometabolic disorders, resulting in significant loss of body fat mass, white adipose tissue browning,</p><p>redistribution of energy substrates, optimization of global energy expenditure, enhancement of</p><p>hypothalamic circuits that control appetite-satiety and energy expenditure, and decreased systemic</p><p>inflammation and insulin resistance. Novel exercise-inducible soluble factors, including myokines,</p><p>hepatokines, and osteokines, and immune cytokines and adipokines are hypothesized to play an</p><p>important role in the body’s response to exercise. To our knowledge, no review has provided a</p><p>comprehensive integrative overview of these novel molecular players and the mechanisms involved</p><p>in the redistribution of metabolic fuel during and after exercise, the loss of weight and fat mass,</p><p>and reduced inflammation. In this review, we explain the potential role of these exercise-inducible</p><p>factors, namely myokines, such as irisin, IL-6, IL-15, METRNL, BAIBA, and myostatin, and hepatokines,</p><p>in particular selenoprotein P, fetuin A, FGF21, ANGPTL4, and follistatin. We also describe the function</p><p>of osteokines, specifically osteocalcin, and of adipokines such as leptin, adiponectin, and resistin.</p><p>We also emphasize an integrative overview of the pleiotropic mechanisms, the metabolic pathways,</p><p>and the inter-organ crosstalk involved in energy expenditure, fat mass loss, reduced inflammation,</p><p>and healthy weight induced by exercise.</p><p>Keywords: exercise; physical activity; fat mass loss; obesity; energy substrate redistribution; myokines;</p><p>hepatokines; osteokines; adipokines; inflammation</p><p>1. Introduction</p><p>Obesity, characterized by abdominal fat gain, is a complex multifactorial disease considered by</p><p>many as a 21st century epidemic [1]. Its incidence is expected to continue given that the energy surplus</p><p>results not only in increased body fat, specially abdominal fat, but also in numerous physiologic</p><p>derangements and cardiometabolic complications and increased morbidity and mortality [1–9].</p><p>Currently considered a cornerstone in the management and prevention of obesity, exercise has been</p><p>demonstrated to have a myriad of health benefits [9,10]. Of concern, less than 5% of adults from the</p><p>U.S. follow the recommended guideline for physical activity of a minimum of 150 min per week [11].</p><p>Evidence suggests that M2 alternatively activated macrophage (M') infiltrates are crucial for beige</p><p>and brown adipose tissue (BAT) activity and that proinflammatory cytokines impair BAT function [12].</p><p>Nutrients 2020, 12, 1899; doi:10.3390/nu12061899 www.mdpi.com/journal/nutrients</p><p>Nutrients 2020, 12, 1899 29 of 48</p><p>Nutrients 2020, 12, x FOR PEER REVIEW 30 of 51</p><p>�</p><p>Figure 5. An integrated view of the role of exercise training on pathways associated with energy</p><p>expenditure, fat mass loss, redistribution of energy substrates, adipose tissue reserves, and</p><p>immunometabolic health: integrated neuroendocrine pathways associated with exercise training that</p><p>affect global AT reserves and function. Interdependence between the processes of central control of</p><p>energy balance, WAT browning, inflammation, and insulin sensitivity is highlighted. AT: adipose</p><p>tissue, ANGPTL4: Angiopoietin-like 4; BAIBA: Ά-Aminoisobutyric acid; BAT: Brown (and beige)</p><p>adipose tissue; EE: Energy expenditure; ER: Endoplasmic reticulum; FAO: Fatty acid oxidation; FI:</p><p>Food intake; FGF21: Fibroblast growth factor 21; GH: Growth hormone; GLP-1: Glucagon-like peptide</p><p>1; IL-1Ra: Interleukin-1 receptor antagonist; IL-1Ά: Interleukin-1Ά; IL-6: Interleukin-6; IL-10:</p><p>Interleukin-10 IL-15: Interleukin-15; MCP-1: Monocyte chemoattractant protein-1; METRNL:</p><p>Meteorin-like; OCN: Osteocalcin; OS: Oxidative stress; ROS: Reactive oxygen species; SNS:</p><p>Sympathetic nervous system; TNF-΅: Tumor necrosis factor alpha; VAT: Visceral adipose tissue.</p><p>Green arrows represent a stimulatory effect over another mediator; red inhibitor lines represent an</p><p>inhibitory effect over another mediator; black arrows or inhibitor lines indicate the final physiologic</p><p>effect of any given mediator, either stimulatory or inhibitory, respectively; blue arrow or inhibitor</p><p>lines indicate the consequence of a process as a whole, either stimulatory or inhibitory, respectively;</p><p>orange inhibitor lines indicate the final processes in the control of fat mass; dotted lines indicate</p><p>absence of an expected effect, either stimulatory or inhibitory. Custom image created with Biorender.</p><p>Figure 5. An integrated view of the role of exercise training on pathways associated with</p><p>energy expenditure, fat mass loss, redistribution of energy substrates, adipose tissue reserves, and</p><p>immunometabolic health: integrated neuroendocrine pathways associated with exercise training that</p><p>a↵ect global AT reserves and function. Interdependence between the processes of central control of</p><p>energy balance, WAT browning, inflammation, and insulin sensitivity is highlighted. AT: adipose tissue,</p><p>ANGPTL4: Angiopoietin-like 4; BAIBA: �-Aminoisobutyric acid; BAT: Brown (and beige) adipose</p><p>tissue; EE: Energy expenditure; ER: Endoplasmic reticulum; FAO: Fatty acid oxidation; FI: Food intake;</p><p>FGF21: Fibroblast growth factor 21; GH: Growth hormone; GLP-1: Glucagon-like peptide 1; IL-1Ra:</p><p>Interleukin-1 receptor antagonist; IL-1�: Interleukin-1�; IL-6: Interleukin-6; IL-10: Interleukin-10</p><p>IL-15: Interleukin-15; MCP-1: Monocyte chemoattractant protein-1; METRNL: Meteorin-like; OCN:</p><p>Osteocalcin; OS: Oxidative stress; ROS: Reactive oxygen species; SNS: Sympathetic nervous system;</p><p>TNF-↵: Tumor necrosis factor alpha; VAT: Visceral adipose tissue. Green arrows represent a stimulatory</p><p>e↵ect over another mediator; red inhibitor lines represent an inhibitory e↵ect over another mediator;</p><p>black arrows or inhibitor lines indicate the final physiologic e↵ect of any given mediator, either</p><p>stimulatory or inhibitory, respectively; blue arrow or inhibitor lines indicate the consequence of a</p><p>process as a whole, either stimulatory or inhibitory, respectively; orange inhibitor lines indicate the</p><p>final processes in the control of fat mass; dotted lines indicate absence of an expected e↵ect, either</p><p>stimulatory or inhibitory. Custom image created with Biorender.</p><p>Está tudo interligado...</p><p>SYSTEMATIC REVIEW</p><p>Dietary Intake of Competitive Bodybuilders</p><p>Jessica Spendlove1 • Lachlan Mitchell1 • Janelle Gifford1 • Daniel Hackett1 •</p><p>Gary Slater2 • Stephen Cobley1 • Helen O’Connor1</p><p>Published online: 30 April 2015</p><p>! Springer International Publishing Switzerland 2015</p><p>Abstract</p><p>Background Competitive bodybuilders are well known</p><p>for extreme physique traits and extremes in diet and</p><p>training manipulation to optimize lean mass and achieve a</p><p>low body fat. Although many of the dietary dogmas in</p><p>bodybuilding lack scientific scrutiny, a number, including</p><p>timing and dosing of high biological value proteins across</p><p>the day, have more recently been confirmed as effective by</p><p>empirical research studies. A more comprehensive under-</p><p>standing of the dietary intakes of bodybuilders has the</p><p>potential to uncover other dietary approaches, deserving of</p><p>scientific investigation, with application to the wider</p><p>sporting, and potential health contexts, where manipulation</p><p>of physique traits is desired.</p><p>Objective Our objective was to conduct a systematic re-</p><p>view of dietary intake practices of competitive body-</p><p>builders, evaluate the quality</p><p>and currency of the existing</p><p>literature, and identify research gaps to inform future</p><p>studies.</p><p>Methods A systematic search of electronic databases was</p><p>conducted from the earliest record until March 2014. The</p><p>search combined permutations of the terms ‘bodybuilding’,</p><p>‘dietary intake’, and ‘dietary supplement’. Included studies</p><p>needed to report quantitative data (energy and</p><p>macronutrients at a minimum) on habitual dietary intake of</p><p>competitive bodybuilders.</p><p>Results The 18 manuscripts meeting eligibility criteria</p><p>reported on 385 participants (n = 62 women). Most studies</p><p>were published in the 1980–1990s, with three published in</p><p>the past 5 years. Study methodological quality was</p><p>evaluated as poor. Energy intake ranged from 10 to</p><p>24 MJ/day for men and from 4 to 14 MJ/day for women.</p><p>Protein intake ranged from 1.9 to 4.3 g/kg for men and from</p><p>0.8 to 2.8 g/kg for women. Intake of carbohydrate and fat</p><p>was\6 g/kg/day and below 30 % of energy, respectively.</p><p>Carbohydrate intakes were below, and protein (in men)</p><p>intakes were higher than, the current recommendations for</p><p>strength athletes, with no consideration for exploration of</p><p>macronutrient quality or distribution over the day. Energy</p><p>intakes varied over different phases of preparation, typically</p><p>being highest in the non-competition ([6 months from</p><p>competition) or immediate post-competition period and</p><p>lowest during competition preparation (B6 months from</p><p>competition) or competition week. The most commonly</p><p>reported dietary supplements were protein powders/liquids</p><p>and amino acids. The studies failed to provide details on</p><p>rationale for different dietary intakes. The contribution of</p><p>diet supplements was also often not reported. When sup-</p><p>plements were reported, intakes of some micronutrients</p><p>were excessive (*1000 % of US Recommended Dietary</p><p>Allowance) and above the tolerable upper limit.</p><p>Conclusion This review demonstrates that literature de-</p><p>scribing the dietary intake practices of competitive body-</p><p>builders is dated and often of poor quality. Intake reporting</p><p>required better specificity and details of the rationale</p><p>underpinning the use. The review suggests that high-qual-</p><p>ity contemporary research is needed in this area, with the</p><p>potential to uncover dietary strategies worthy of scientific</p><p>exploration.</p><p>& Helen O’Connor</p><p>Helen.OConnor@sydney.edu.au</p><p>Jessica Spendlove</p><p>jspe5967@uni.sydney.edu.au</p><p>1 Discipline of Exercise and Sport Science, Faculty of Health</p><p>Sciences, The University of Sydney, 75 East St, Lidcombe,</p><p>NSW 2141, Australia</p><p>2 University of the Sunshine Coast at Sippy Downs,</p><p>Sippy Downs, QLD, Australia</p><p>123</p><p>Sports Med (2015) 45:1041–1063</p><p>DOI 10.1007/s40279-015-0329-4</p><p>sports</p><p>Review</p><p>Nutrition Recommendations for Bodybuilders in the</p><p>O↵-Season: A Narrative Review</p><p>Juma Iraki 1,*, Peter Fitschen 2, Sergio Espinar 1 and Eric Helms 3</p><p>1 Iraki Nutrition AS, 2008 Fjerdingby, Norway</p><p>2 Fitbody and Physique LLC, Stevens Point, WI 54481, USA</p><p>3 Sport Performance Research Institute New Zealand (SPRINZ) at AUT Millennium, Auckland University of</p><p>Technology, Auckland 0632, New Zealand</p><p>* Correspondence: juma@irakinutrition.com; Tel.: +47-47-44-36-44</p><p>Received: 20 May 2019; Accepted: 24 June 2019; Published: 26 June 2019</p><p>!"#!$%&'(!</p><p>!"#$%&'</p><p>Abstract: Many nutrition practices often used by bodybuilders lack scientific support and can be</p><p>detrimental to health. Recommendations during the dieting phase are provided in the scientific</p><p>literature, but little attention has been devoted to bodybuilders during the o↵-season phase. During</p><p>the o↵-season phase, the goal is to increase muscle mass without adding unnecessary body fat.</p><p>This review evaluated the scientific literature and provides nutrition and dietary supplement</p><p>recommendations for natural bodybuilders during the o↵-season phase. A hyper-energetic diet</p><p>(~10–20%) should be consumed with a target weight gain of ~0.25–0.5% of bodyweight/week for</p><p>novice/intermediate bodybuilders. Advanced bodybuilders should be more conservative with the</p><p>caloric surplus and weekly weight gain. Su�cient protein (1.6–2.2 g/kg/day) should be consumed</p><p>with optimal amounts 0.40–0.55 g/kg per meal and distributed evenly throughout the day (3–6 meals)</p><p>including within 1–2 hours pre- and post-training. Fat should be consumed in moderate amounts</p><p>(0.5–1.5 g/kg/day). Remaining calories should come from carbohydrates with focus on consuming</p><p>su�cient amounts (�3–5 g/kg/day) to support energy demands from resistance exercise. Creatine</p><p>monohydrate (3–5 g/day), ca↵eine (5–6 mg/kg), beta-alanine (3–5 g/day) and citrulline malate (8 g/day)</p><p>might yield ergogenic e↵ects that can be beneficial for bodybuilders.</p><p>Keywords: Bodybuilding; nutrition; muscle hypertrophy</p><p>1. Introduction</p><p>Bodybuilding is more than a sport; it is an art and culture. It di↵erentiates itself from performance</p><p>sports as the athletes are judged on appearance rather than athletic ability on competition day.</p><p>Bodybuilders pose onstage where they are judged on muscularity, definition, and symmetry. During a</p><p>season, bodybuilders go through three di↵erent phases: muscle-gaining phase (o↵-season), dieting</p><p>for competition (contest preparation) and the competition itself. Most of the literature surrounds the</p><p>dieting phase [1].</p><p>However, the scientific literature on dietary recommendations for bodybuilders in the o↵-season</p><p>is lacking. This is an important gap, as most of a bodybuilder’s career is spent in this phase where</p><p>the goal is to increase muscle mass while minimizing excess increases in fat mass. Bodybuilders</p><p>are known for having rigid attitudes toward food selection, meal frequency, nutrition timing and</p><p>supplementation [2]. Historically, information about nutrition and supplementation has been passed</p><p>on by bodybuilding magazines and successful competitors, but recently more information has emerged</p><p>via the internet and forums [3,4]. As such, many of the dietary strategies used by bodybuilders do not</p><p>have sound scientific support and there is evidence in the scientific literature that a number of these</p><p>strategies, including the heavy use of dietary supplements, can be detrimental to health [5–7].</p><p>Sports 2019, 7, 154; doi:10.3390/sports7070154 www.mdpi.com/journal/sports</p><p>sports</p><p>Article</p><p>Do Bodybuilders Use Evidence-Based Nutrition</p><p>Strategies to Manipulate Physique?</p><p>Lachlan Mitchell 1,* ID , Daniel Hackett 1 ID , Janelle Gifford 1, Frederico Estermann 1</p><p>and Helen O’Connor 1,2 ID</p><p>1 Discipline of Exercise and Sport Science, Faculty of Health Sciences, University of Sydney, 75 East Street,</p><p>Lidcombe NSW 2141, Australia; daniel.hackett@sydney.edu.au (D.H.); janelle.gifford@sydney.edu.au (J.G.);</p><p>fest5296@uni.sydney.edu.au (F.E.); helen.oconnor@sydney.edu.au (H.O.C.)</p><p>2 Charles Perkins Centre, University of Sydney, D17 John Hopkins Drive, Camperdown NSW 2050, Australia</p><p>* Correspondence: lachlan.mitchell@sydney.edu.au; Tel.: +61-2-9036-7358</p><p>Received: 4 September 2017; Accepted: 26 September 2017; Published: 29 September 2017</p><p>Abstract: Competitive bodybuilders undergo strict dietary and training practices to achieve an</p><p>extremely lean and muscular physique. The purpose of this study was to identify and describe</p><p>different dietary strategies used by bodybuilders, their rationale, and the sources of information from</p><p>which these strategies are gathered. In-depth interviews were conducted with seven experienced</p><p>(10.4 ± 3.4 years bodybuilding experience), male, natural bodybuilders. Participants were asked about</p><p>training, dietary and supplement practices, and information resources for bodybuilding strategies.</p><p>Interviews were transcribed verbatim and analyzed using qualitative content analysis. During the</p><p>off-season, energy intake was higher and less restricted than during the in-season to aid in muscle</p><p>hypertrophy. There was a focus on high protein intake with adequate carbohydrate to permit high</p><p>training loads. To create an energy deficit and loss of fat mass, energy intake was gradually and</p><p>progressively reduced during the in-season via a reduction in carbohydrate and fat</p><p>intake. The rationale</p><p>for weekly higher carbohydrate refeed days was to offset declines in metabolic rate and fatigue, while</p><p>in the final “peak week” before competition, the reasoning for fluid and sodium manipulation and</p><p>carbohydrate loading was to enhance the appearance of leanness and vascularity. Other bodybuilders,</p><p>coaches and the internet were significant sources of information. Despite the common perception of</p><p>extreme, non-evidence-based regimens, these bodybuilders reported predominantly using strategies</p><p>which are recognized as evidence-based, developed over many years of experience. Additionally,</p><p>novel strategies such as weekly refeed days to enhance fat loss, and sodium and fluid manipulation,</p><p>warrant further investigation to evaluate their efficacy and safety.</p><p>Keywords: protein; peak week; refeed day; supplement</p><p>1. Introduction</p><p>Competitive bodybuilders undergo strict dietary and training practices to achieve an extremely</p><p>lean, muscular and symmetrical physique [1]. Along with resistance and aerobic exercise [2], targeted</p><p>energy and macronutrient intakes are followed to accumulate muscle mass in the off-season, and</p><p>reduce fat mass in the in-season [1]. However the specific dietary strategies employed by bodybuilders</p><p>and their underpinning rationale remain poorly understood.</p><p>Contemporary literature examining the dietary intakes of bodybuilders is limited [1], and given</p><p>the unique nature of competitive bodybuilding, it may be inappropriate to draw dietary parallels</p><p>from other sports. Although bodybuilders have been reported to follow extreme, non-evidence-based</p><p>approaches, several dietary strategies developed in bodybuilding have recently been scientifically</p><p>validated, such as frequent dosing of protein [3], and intake of protein around training [4]. Identifying</p><p>Sports 2017, 5, 76; doi:10.3390/sports5040076 www.mdpi.com/journal/sports</p><p>Sports Med 2004; 34 (5): 317-327REVIEW ARTICLE 0112-1642/04/0005-0317/$31.00/0</p><p> 2004 Adis Data Information BV. All rights reserved.</p><p>Macronutrient Considerations for the</p><p>Sport of Bodybuilding</p><p>Charles P. Lambert,1 Laura L. Frank2 and William J. Evans1</p><p>1 Nutrition, Metabolism, and Exercise Laboratory, Donald W. Reynolds Center on Aging,</p><p>Department of Geriatrics, University of Arkansas for Medical Sciences and Geriatric Research,</p><p>Education and Clinical Center, Central Arkansas Veterans Healthcare System, Little Rock,</p><p>Arkansas, USA</p><p>2 Department of Psychiatry and Behavioral Sciences, University of Washington School of</p><p>Medicine and Geriatric Research, Education and Clinical Center, Puget Sound Health Care</p><p>System, Seattle, Washington, USA</p><p>Contents</p><p>Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317</p><p>1. Macronutrient Composition for Optimal Muscle Mass Accretion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318</p><p>1.1 Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318</p><p>1.2 Carbohydrate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 319</p><p>1.3 Fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320</p><p>2. Efficacy of a Positive Energy Balance on Resistance Exercise-Induced Gains in Muscle Mass . . . . 320</p><p>3. Timing of Amino Acid/Protein Intake Following Resistance Exercise . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321</p><p>4. Optimal Post-Exercise Nutrition to Maximise the Rate of Muscle Glycogen Repletion . . . . . . . . . . . . 322</p><p>5. Optimal Macronutrient Composition for Fat Loss and Muscle Mass Maintenance . . . . . . . . . . . . . . . 323</p><p>6. Recommendations for Pre- and Post-Training Session Nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325</p><p>7. Factors Influencing Fat-Free Mass Loss During Energy Restriction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325</p><p>8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325</p><p>Participants in the sport of bodybuilding are judged by appearance rather thanAbstract</p><p>performance. In this respect, increased muscle size and definition are critical</p><p>elements of success. The purpose of this review is to evaluate the literature and</p><p>provide recommendations regarding macronutrient intake during both</p><p>‘off-season’ and ‘pre-contest’ phases. Body builders attempt to increase muscle</p><p>mass during the off-season (no competitive events), which may be the great</p><p>majority of the year. During the off-season, it is advantageous for the bodybuilder</p><p>to be in positive energy balance so that extra energy is available for muscle</p><p>anabolism. Additionally, during the off-season, adequate protein must be avail-</p><p>able to provide amino acids for protein synthesis. For 6–12 weeks prior to</p><p>competition, body builders attempt to retain muscle mass and reduce body fat to</p><p>very low levels. During the pre-contest phase, the bodybuilder should be in</p><p>negative energy balance so that body fat can be oxidised. Furthermore, during the</p><p>pre-contest phase, protein intake must be adequate to maintain muscle mass.</p><p>There is evidence that a relatively high protein intake (~30% of energy intake) will</p><p>reduce lean mass loss relative to a lower protein intake (~15% of energy intake)</p><p>VAMOS AJUDÁ-LO?</p><p>Homem 100kg</p><p>5477kcal</p><p>+</p><p>500kcal-1000kcal</p><p>(adicional 10-20% do total)</p><p>=</p><p>6000kcal-7000kcal/dia</p><p>126kg</p><p>15,6% de gordura</p><p>Massa magra (ossos, órgãos e</p><p>músculos) = 106,4kg</p><p>Peso (kg) músculo = 63kg</p><p>Peso gordura = 19,6kg</p><p>126kg x 60kcal = 7.560kcal</p><p>126kg x 10g carbo/kg = 1260g = 5040kcal</p><p>126kg x 2,5g prot/kg = 315g = 1260kcal</p><p>126kg x 1,2g lip/kg = 151,2g = 1360kcal</p><p>TOTAL = 7660kcal</p><p>RELAÇÃO gNitrogenio/kcal</p><p>(carbo + gordura) = 6400kcal</p><p>/ 50g nitrogênio (315g ptn) =</p><p>128kcal/g de nitrogênio (+)</p><p>Partiu Atacadão</p><p>Alimentos fontes de carbo</p><p>2,7kg de arroz branco</p><p>cozido</p><p>11 bananas</p><p>320g de aveia</p><p>1 litro de suco de laranja</p><p>200g de sucrilhos</p><p>100g de doce de leite</p><p>60ml de mel</p><p>Alimentos fontes de proteca</p><p>24 ovos</p><p>520g de frango</p><p>3 doses de whey</p><p>Alimentos fontes de gordura</p><p>40ml de azeite</p><p>60g de pasta</p><p>8 refeições = Macros/ refeição = 959kcal/ref</p><p>Proteina = 40g = 160kcal</p><p>Carboidrato = 157g = 628kcal</p><p>Lipídios = 19g= 171kcal</p><p>Treino</p><p>REFEIÇAO 1</p><p>2 ovos + 10 claras</p><p>200g de banana + 80g</p><p>de aveia + 30ml mel +</p><p>50g sucrilhos</p><p>REFEIÇAO 2</p><p>390g de arroz branco cozido</p><p>100g de banana</p><p>250ml de suco de laranja</p><p>130g filet de frango</p><p>10ml de azeite</p><p>REFEIÇAO 3</p><p>30g de pasta amendoim + 1</p><p>dose ½ de whey protein</p><p>200g de banana + 80g de</p><p>aveia + 50g doce de leite +</p><p>50g sucrilhos</p><p>REFEIÇAO 4</p><p>390g de arroz branco cozido</p><p>100g de banana</p><p>250ml de suco de laranja</p><p>130g filet de frango</p><p>10ml de azeite</p><p>REFEIÇAO 5</p><p>30g de pasta amendoim + 1</p><p>dose ½ de whey protein</p><p>200g de banana + 80g de</p><p>aveia + 50g doce de leite +</p><p>50g sucrilhos</p><p>REFEIÇAO 6</p><p>390g de arroz branco cozido</p><p>100g de banana</p><p>250ml de suco de laranja</p><p>130g filet de frango</p><p>10ml de azeite</p><p>REFEIÇAO 7</p><p>390g de arroz branco cozido</p><p>100g de banana</p><p>250ml de suco de laranja</p><p>130g filet de frango</p><p>10ml de azeite</p><p>REFEIÇAO 8</p><p>2 ovos + 10 claras</p><p>200g de banana + 80g</p><p>de aveia + 30ml mel +</p><p>50g sucrilhos</p><p>BETA-ALANINACREATINA</p><p>PROTEÍNAS</p><p>CARBOIDRATOS</p><p>OMEGA 3</p><p>VIT.D</p><p>FITOTERÁPICOS</p><p>ADAPTÓGENOS</p><p>“DANONE/SUCO”</p><p>RECURSOS.</p><p>ERGOGÊNICOS.</p><p>FARMACOLÓGICOS.</p><p>ÁGUA</p><p>SIMBIÓTICOS</p><p>Quanto mais você come, mais</p><p>você precisa comer!!!</p><p>LIÇÃO PARA CASA</p><p>www.felipedonatto.com.br</p><p>NUTRICIONISTA</p><p>BRASILEIRO(A)</p><p>É UM DOS MELHORES</p><p>DO MUNDO!!</p><p>http://dx.doi.org/10.1016/j.cyto.2012.10.021</p><p>⇑ Corresponding author. Address: Av. Prof. Lineu Prestes, 1524, CEP 05508-900</p><p>Butanta, São Paulo, Brazil. Fax: +55 011 3091 7402.</p><p>E-mail address: seelaend@icb.usp.br (M. Seelaender).</p><p>Cytokine 61 (2013) 426–432</p><p>Contents lists available at SciVerse ScienceDirect</p><p>Cytokine</p><p>journal homepage: www.journals .e lsevier .com/cytokine</p><p>homogenised in RIPA buffer (0.625% Nonidet P-40, 0.625% sodium</p><p>deoxycholate, 6.25 mM sodium phosphate, and 1 mM ethylenedia-</p><p>mine tetraacetic acid at pH 7.4) containing 10 Lg/mL of protease</p><p>inhibitor cocktail (Sigma–Aldrich, St. Louis, Missouri). Homoge-</p><p>nates were centrifuged at 12,000g for 10 min at 4 C, the superna-</p><p>tant was saved, and protein concentration was determined by</p><p>Bradford assay (Bio-Rad, Hercules, CA) with bovine serum albumin</p><p>as a reference. For the TNF-a (DY510), IL-6 (DY506) and IL-10</p><p>(DY522) assays, sensitivity was found to be 5.0 pg/mL in the range</p><p>of 31.2–2.000 pg/mL. Assay sensitivity for IL-10 was 10 pg/mL in</p><p>the range from 31.2 to 2.000 pg/mL. All samples were run as dupli-</p><p>cates, and the mean value was reported.</p><p>3. Statistical treatment</p><p>Data are presented as means ± standard deviation (SD). Statisti-</p><p>cal analysis was performed with Student’s T test for resistance pro-</p><p>tocol progress and 2-way analysis of variance (2-way ANOVA) with</p><p>exercise and tumour as factors. All variables presented normal dis-</p><p>tribution and homoscedasticity, when t difference was found to be</p><p>significant, Tukey’s post hoc test was adopted. A significance level</p><p>of p 6 0.05 was employed for all comparisons. Statistical analysis</p><p>was carried out with GraphPad prism software, version 5.0 (Graph-</p><p>Pad Software, San Diego, CA).</p><p>4. Results</p><p>4.1. Tissue weigtht</p><p>Table 1 illustrates the values of body weight before and after the</p><p>training period, as well as the absolute retroperitoneal adipose tis-</p><p>sue (RPAT), mesenteric adipose tissue (MEAT), epididymal adipose</p><p>tissue (EPAT), and gastrocnemius weights. Resistance training in-</p><p>creased body weight gain of RTTB, when compared with TB (9%</p><p>p < 0.048), along with higher absolute gastrocnemius muscle</p><p>weight (26% p < 0.027). RPAT showed statistical difference in TB</p><p>and RTTB when compared with Control. (30%; p < 0.002 and 56%</p><p>p < 0.001), showing that both the presence of the tumour and the</p><p>exercise protocol influence this parameter. Tumour mass was de-</p><p>creased after exercise, yet the difference did not reach statistical</p><p>significance.</p><p>4.2. Resistance training progress chart</p><p>Fig. 1 illustrates the progress of resistance training overload</p><p>during the experimental period. A separate RT group was run to</p><p>compare the maximal repetition (1-RM) evolution in the absence</p><p>of the tumour. After tumour inoculation induced a decrease in total</p><p>work performed (initial 6th week). RTTB presented reduced perfor-</p><p>mance by 10% (p < 0.05), when compared with RT in the 6th, 7th</p><p>and 8th weeks of the exercise protocol.</p><p>4.3. Plasma biochemistry</p><p>The analysis of the plasma (Table 2) demonstrates a reduction</p><p>of glycaemia in RTTB, when compared with CT (21%; p < 0.006)</p><p>and TB (20%; p < 0.008). With respect to TAG, TB levels were 29%</p><p>(p < 0.02) higher then CT’s and no significant difference was de-</p><p>tected regarding RTTB. The Lipoprotein profile presented heteroge-</p><p>neous results: in relation to VLDL-c, there was an increase of 30%</p><p>(p < 0.03) in TB compared with CT. The parameter was not different</p><p>among RTTB, CT and TB. LDL-c levels were decreased in RTTB by</p><p>43% (p < 0.029), when compared with TB, while no difference was</p><p>found for CT. HDL-c levels were increased in RTTB by 15%</p><p>(p < 0.049) compared with CT and 22% (p < 0.005), as compared</p><p>with TB. Creatinine and LDH activity did not show significant var-</p><p>iation among the experimental groups. With respect to hormones,</p><p>testosterone was shown to be 55% (p < 0.042) and 63% (p < 0.03)</p><p>higher, in RTTB compared with CT and TB, respectively.</p><p>Table 1</p><p>Body weight, adipose tissue and gastrocnemius weight.</p><p>Experimental groups CT TB RT RTTB</p><p>Initial body weight (g) 209.3 ± 3.2 216.5 ± 4.9 208.6 ± 7.9 211.2 ± 2.8</p><p>Final body weight (g) 335.6 ± 3.4 288.3 ± 4.9a 348.5 ± 10.9b 310.8 ± 9.8b</p><p>Final tumour weight (g) – 32 ± 0.8 – 19,6 ± 0.5</p><p>Absolute EPAT (g) 3.6 ± 0.3 3.28 ± 0.7 2.96 ± 0.9 3.06 ± 0.3</p><p>Absolute MEAT (g) 1.74 ± 0.3 2.19 ± 0.4 1.89 ± 0.7 2.09 ± 0.4</p><p>Absolute RPAT (g) 3.16 ± 1.2 2.22 ± 0.2a 2.14 ± 0.4a 2.02 ± 0.7a</p><p>Absolute</p><p>gastrocnemius (g)</p><p>2.65 ± 0.3 1.72 ± 0.1a 2.75 ± 0.4ab 2.30 ± 0.2b</p><p>Values are mean ± SD; initial and final body mass; absolute weight of the adipose</p><p>tissues: Epididymal adipose tissue (EPAT), Mesenteric adipose tissue (MEAT) and</p><p>Retroperitoneal adipose tissue (RPAT); tumour and gastrocnemius. CT (control), TB</p><p>(tumour-bearing), RT (resistance training) and RTTB (resistance training tumour-</p><p>bearing). Values that are significantly different by two-way ANOVA are indicated.</p><p>a p < 0.05 compared with control.</p><p>b p < 0.05 compared with TB.</p><p>Fig. 1. RM evolution along the exercise protocol. Values are mean ± SD; RM</p><p>(repetition maximum); RT (resistance training) and RTTB (resistance training</p><p>tumour-bearing). Values that are significantly different by test t. !p < 0.05 compared</p><p>with RT.</p><p>Table 2</p><p>Plasma biochemical profile of experimental groups.</p><p>Parameters CT TB RT RTTTB</p><p>Glucose (mmol/L) 4.5 ± 0.2 4.6 ± 0.01 4.02 ± 0.2 3.8 ± 0.3a,b</p><p>Cholesterol (mmol/L) 2.49 ± 0.7 2.61 ± 0.4 2.37 ± 0.03 2.57 ± 0.2</p><p>TAG (mmol/L) 1.11 ± 0.07 1.44 ± 0.1a 1.03 ± 0.02a,b 1.24 ± 0.2</p><p>VLDL-c (mmol/L) 0.49 ± 0.03 0.64 ± 0.01a 0.46 ± 0.01b 0.55 ± 0.13</p><p>LDL-c (mmol/L) 0.49 ± 0.6 0.57 ± 0.1 0.24 ± 0.7a,b 0.28 ± 0.9b</p><p>HDL-c (mmol/L) 1.13 ± 0.7 1.07 ± 0.07 1.33 ± 0.13a,b 1.31 ± 0.12a,b</p><p>Creatinine (lmol/L) 18.96 ± 6.8 14.2 ± 3.2 17.85 ± 2.5 16.88 ± 2.9</p><p>Testosterone (ng/mL) 254 ± 41.3 221 ± 23.1 734 ± 88.2a,b 577 ± 131a,b</p><p>Values are mean ± SD; serum level: Glucose, Cholesterol total, TAG (triacylglycerol),</p><p>VLDL-c (Very low-density lipoprotein), LDL-c (Low-density lipoprotein), HDL-c</p><p>(High-density lipoprotein), Creatinine and testosterone; CT (control), TB (tumour-</p><p>bearing), RT (resistance training) and RTTB (resistance training tumour-bearing).</p><p>Values that are significantly different by two-way ANOVA are indicated by two-way</p><p>ANOVA.</p><p>a p < 0.05 compared with control.</p><p>b p < 0.05 compared with TB.</p><p>428 F.F. Donatto et al. / Cytokine 61 (2013) 426–432</p><p>TREINAMENTO DE FORÇA</p><p>International Journal of</p><p>Molecular Sciences</p><p>Review</p><p>Physical Exercise and Myokines: Relationships with</p><p>Sarcopenia and Cardiovascular Complications</p><p>Sandra Maria Barbalho</p><p>1,2,3,</p><p>* , Uri Adrian Prync Flato</p><p>1,2</p><p>, Ricardo José Tofano</p><p>1,2</p><p>,</p><p>Ricardo de Alvares Goulart</p><p>1</p><p>, Elen Landgraf Guiguer</p><p>1,2,3</p><p>, Cláudia Rucco P. Detregiachi</p><p>1</p><p>,</p><p>Daniela Vieira Buchaim</p><p>1,4</p><p>, Adriano Cressoni Araújo</p><p>1,2</p><p>, Rogério Leone Buchaim</p><p>1,5</p><p>,</p><p>Fábio Tadeu Rodrigues Reina</p><p>1</p><p>, Piero Biteli</p><p>1</p><p>, Daniela O. B. Rodrigues Reina</p><p>1</p><p>and Marcelo Dib Bechara</p><p>2</p><p>1 Postgraduate Program in Structural and Functional Interactions in Rehabilitation,</p><p>University of Marilia (UNIMAR), Avenue Hygino Muzzy Filho, 1001, Marília 17525-902, São Paulo, Brazil;</p><p>uriflato@gmail.com (U.A.P.F.); rtofano@uol.com.br (R.J.T.); ricardogoulartmed@hotmail.com (R.d.A.G.);</p><p>elguiguer@gmail.com (E.L.G.); claurucco@gmail.com (C.R.P.D.); danielaortega@ig.com.br (D.V.B.);</p><p>adrianocressoniaraujo@yahoo.com.br (A.C.A.); rogerioleonibuchaim@unimar.br (R.L.B.);</p><p>fabioreina@unimar.br (F.T.R.R.); pbiteli@icloud.com (P.B.); danielareina@unimar.br (D.O.B.R.R.)</p><p>2 School of Medicine, University of Marília (UNIMAR), Avenida Higino Muzzi Filho, 1001,</p><p>Marília 17506-000, São Paulo, Brazil; dib.marcelo1@gmail.com</p><p>3 Department of Biochemistry and Nutrition, Food Technology School, Marília 17525-902, São Paulo, Brazil</p><p>4 Medical School, University Center of Adamantina (UniFAI), Adamantina 17800-000, São Paulo, Brazil</p><p>5 Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo (FOB–USP),</p><p>Alameda Doutor Octávio Pinheiro Brisolla, 9-75, Bauru 17012901, São Paulo, Brazil</p><p>* Correspondence:</p><p>smbarbalho@gmail.com; Tel.: +55-14-99655-3190</p><p>Received: 6 May 2020; Accepted: 19 May 2020; Published: 20 May 2020</p><p>!"#!$%&'(!</p><p>!"#$%&'</p><p>Abstract: Skeletal muscle is capable of secreting di↵erent factors in order to communicate with other</p><p>tissues. These mediators, the myokines, show potentially far-reaching e↵ects on non-muscle tissues</p><p>and can provide a molecular interaction between muscle and body physiology. Sarcopenia is a</p><p>chronic degenerative neuromuscular disease closely related to cardiomyopathy and chronic heart</p><p>failure, which influences the production and release of myokines. Our objective was to explore</p><p>the relationship between myokines, sarcopenia, and cardiovascular diseases (CVD). The autocrine,</p><p>paracrine, and endocrine actions of myokines include regulation of energy expenditure, insulin</p><p>sensitivity, lipolysis, free fatty acid oxidation, adipocyte browning, glycogenolysis, glycogenesis,</p><p>and general metabolism. A sedentary lifestyle accelerates the aging process and is a risk factor</p><p>for developing sarcopenia, metabolic syndrome, and CVD. Increased adipose tissue resulting from</p><p>the decrease in muscle mass in patients with sarcopenia may also be involved in the pathology</p><p>of CVD. Myokines are protagonists in the complex condition of sarcopenia, which is associated</p><p>with adverse clinical outcomes in patients with CVD. The discovery of new pathways and the link</p><p>between myokines and CVD remain a cornerstone toward multifaceted interventions and perhaps</p><p>the minimization of the damage resulting from muscle loss induced by factors such as atherosclerosis.</p><p>Keywords: sarcopenia; myokines; cardiovascular diseases</p><p>1. Introduction</p><p>Skeletal muscle is the most massive protein reserve in the human body, the primary site of glucose</p><p>metabolism regulation, and the main energy consumer. In addition to glycogenolysis, skeletal muscle</p><p>is degraded during starvation and produces amino acids and lactate that are utilized in hepatic and</p><p>renal gluconeogenesis. Muscles can also release microRNA. Furthermore, skeletal muscle is capable</p><p>Int. J. Mol. Sci. 2020, 21, 3607; doi:10.3390/ijms21103607 www.mdpi.com/journal/ijms</p><p>Int. J. Mol. Sci. 2020, 21, 3607 5 of 15Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 5 of 16</p><p>�</p><p>�</p><p>Figure 1. Systemic effects of some myokines. After resistance exercise, specific myokines, such as</p><p>decorin and IGF-1, are released; after endurance training, other specific myokines, such as myonectin,</p><p>apelin, musclin, and IL-6, are produced and play different roles in different tissues. IGF-1: insulin-like</p><p>growth factor-1; IL-6: interleukin-6; IL-15: interleukin-15; UCP: uncoupling protein; WAT: white</p><p>adipose tissue; GLP-1: glucagon-like peptide-1. Up arrows indicate increase; down arrows indicate</p><p>reduction.</p><p>2.2. Sarcopenia</p><p>Skeletal muscle is very plastic, since it can be modified/enlarged in response to exercise or can</p><p>be substantially reduced in catabolic conditions, such as aging, or diseases, such as diabetes, cancer,</p><p>cardiovascular diseases, chronic obstructive pulmonary disease, and infectious diseases. It is the</p><p>major reservoir of proteins, but in catabolic condition , it can be reduced, leading to cachexia and</p><p>death [15].</p><p>Sarcopenia is a chronic degenerative neuromuscular disease and a debilitating condition related</p><p>to aging, which is characterized by the progressive loss of skeletal muscle, strength, and function. It</p><p>is related to an increase in the risks of falls, fractures, and poor quality of life, which results in</p><p>disability, frailty, and high mortality. Furthermore, sarcopenia is also related to several other health</p><p>conditions, such as cognitive impairment, cardiac and respiratory disease, and osteoporosis. It is</p><p>considered a public health problem, in light of its possible adverse outcomes [39,62,63].</p><p>The decrease in muscle size occurs because of a reduction in cell size (loss of proteins, organelles,</p><p>and cytosol) driven by protein catabolism through amplified lysosomal and proteasomal functions</p><p>activated by FoxO3-dependent transcription and reduced protein production upregulated by the</p><p>IGF-1/PI3K/AKT pathway. This process also causes a reduction of mitochondria and, consequently,</p><p>a reduction in energy production that leads to fatigue [64]. FOXO3a increases the expression of</p><p>human ferritin and upregulates iron transport, leading to iron accumulation, which may negatively</p><p>affect the production of myokines, and enhances motor neuron vulnerability to degeneration [65].</p><p>The interpretation of the measurements to evaluate sarcopenia is challenging, since they</p><p>parameters measured are not muscle-specific or sensitive to the etiology. Also, there are confounding</p><p>elements, such as fitness level and presence of pain and depression. Furthermore, individuals in the</p><p>later stages of sarcopenia might eventually not be able to perform these tests. For these reasons,</p><p>Figure 1. Systemic e↵ects of some myokines. After resistance exercise, specific myokines, such as</p><p>decorin and IGF-1, are released; after endurance training, other specific myokines, such as myonectin,</p><p>apelin, musclin, and IL-6, are produced and play di↵erent roles in di↵erent tissues. IGF-1: insulin-like</p><p>growth factor-1; IL-6: interleukin-6; IL-15: interleukin-15; UCP: uncoupling protein; WAT: white adipose</p><p>tissue; GLP-1: glucagon-like peptide-1. Up arrows indicate increase; down arrows indicate reduction.</p><p>2.2. Sarcopenia</p><p>Skeletal muscle is very plastic, since it can be modified/enlarged in response to exercise or can</p><p>be substantially reduced in catabolic conditions, such as aging, or diseases, such as diabetes, cancer,</p><p>cardiovascular diseases, chronic obstructive pulmonary disease, and infectious diseases. It is the major</p><p>reservoir of proteins, but in catabolic condition, it can be reduced, leading to cachexia and death [15].</p><p>Sarcopenia is a chronic degenerative neuromuscular disease and a debilitating condition related</p><p>to aging, which is characterized by the progressive loss of skeletal muscle, strength, and function. It is</p><p>related to an increase in the risks of falls, fractures, and poor quality of life, which results in disability,</p><p>frailty, and high mortality. Furthermore, sarcopenia is also related to several other health conditions,</p><p>such as cognitive impairment, cardiac and respiratory disease, and osteoporosis. It is considered</p><p>a public health problem, in light of its possible adverse outcomes [39,62,63].</p><p>The decrease in muscle size occurs because of a reduction in cell size (loss of proteins, organelles,</p><p>and cytosol) driven by protein catabolism through amplified lysosomal and proteasomal functions</p><p>activated by FoxO3-dependent transcription and reduced protein production upregulated by the</p><p>IGF-1/PI3K/AKT pathway. This process also causes a reduction of mitochondria and, consequently,</p><p>a reduction in energy production that leads to fatigue [64]. FOXO3a increases the expression of human</p><p>ferritin and upregulates iron transport, leading to iron accumulation, which may negatively a↵ect the</p><p>production of myokines, and enhances motor neuron vulnerability to degeneration [65].</p><p>The interpretation of the measurements to evaluate sarcopenia is challenging, since they parameters</p><p>measured are not muscle-specific or sensitive to the etiology. Also, there are confounding elements,</p><p>such as fitness level and presence of pain and depression. Furthermore, individuals in the later</p><p>stages of sarcopenia might eventually not be able to perform these tests. For these reasons, e↵ective</p><p>diagnosis, treatment, and follow-up should be accompanied by the evaluation of muscle-specific</p><p>biomarkers [7,66].</p><p>Int. J. Mol. Sci. 2020, 21, 3607 7 of 15</p><p>Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 7 of 16</p><p>�</p><p>Figure 2. Aging process: (1) sarcopenia and its consequences and (2) influence of exercise on the</p><p>release of myokines. BMP-7: bone morphogenetic factor-7; IL-15: interleukin-15; IGF-1: insulin-like</p><p>growth factor-1; GDF-15: growth/differentiation factor-15 BDNF: brain-derived neurotrophic factor;</p><p>QoL: quality of life.</p><p>Son et al. [82] suggested that both irisin and SPARC could work as therapeutic mediators to</p><p>avoid muscle atrophy and sarcopenia.</p><p>2.3. Myokines, Sarcopenia, and Cardiovascular Diseases</p><p>Despite countless advances in medicine and correlated areas, the management of chronic disease</p><p>is a challenge for professionals. Aging leads to physiological modifications in body composition,</p><p>affecting disease outcomes and amplification of the burden to both public and private healthcare. As</p><p>pointed out above, the physical adjustments related to age involve, for example, sarcopenia [83,84].</p><p>The aging process is associated with impairments in cardiovascular function, muscular strength,</p><p>and cognitive ability. Mitochondrial dysfunction, reduction in protein synthesis and peroxisome</p><p>PGC-1΅ levels, as well as their consequences such as protein degradation, atrophy, denervation, a</p><p>shift of fatty acid oxidation to higher dependence on carbohydrates result in cardiomyopathy and</p><p>other cardiovascular complications. The loss of muscle mass in individuals with chronic heart disease</p><p>increases the risk of death [85].</p><p>Many studies bring to light that sarcopenia shares several pathophysiologic aspects with heart</p><p>diseases in older adults. Sarcopenia is independently related to prevalent cardiovascular disorders,</p><p>such as myocardial infarction, congestive heart failure, atrial fibrillation, atherosclerosis, and related</p><p>risk factors [86,87].</p><p>In a cross-sectional study [67], it was shown that there is a significant impact of sarcopenia on</p><p>the occurrence of stroke in elderly individuals. In another study with 316 elderly patients with stroke,</p><p>Nozoe et al. [88] showed that the appearance of pre-stroke sarcopenia is an independent predictor of</p><p>moderate to severe stroke.</p><p>Anaszewicz et al. [89] in a cohort study showed that patients with atrial fibrillation had a higher</p><p>body mass index, larger waist circumference and visceral adiposity, higher values for fat and fat-free</p><p>Figure 2. Aging process: (1) sarcopenia and its consequences and (2) influence of exercise on the</p><p>release of myokines. BMP-7: bone morphogenetic factor-7; IL-15: interleukin-15; IGF-1: insulin-like</p><p>growth factor-1; GDF-15: growth/di↵erentiation factor-15 BDNF: brain-derived neurotrophic factor;</p><p>QoL: quality of life.</p><p>2.3. Myokines, Sarcopenia, and Cardiovascular Diseases</p><p>Despite countless advances in medicine and correlated areas, the management of chronic disease</p><p>is a challenge for professionals. Aging leads to physiological modifications in body composition,</p><p>a↵ecting disease outcomes and amplification of the burden to both public and private healthcare.</p><p>As pointed out above, the physical adjustments related to age involve, for example, sarcopenia [83,84].</p><p>The aging process is associated with impairments in cardiovascular function, muscular strength,</p><p>and cognitive ability. Mitochondrial dysfunction, reduction in protein synthesis and peroxisome</p><p>PGC-1↵ levels, as well as their consequences such as protein degradation, atrophy, denervation, a shift</p><p>of fatty acid oxidation to higher dependence on carbohydrates result in cardiomyopathy and other</p><p>cardiovascular complications. The loss of muscle mass in individuals with chronic heart disease</p><p>increases the risk of death [85].</p><p>Many studies bring to light that sarcopenia shares several pathophysiologic aspects with heart</p><p>diseases in older adults. Sarcopenia is independently related to prevalent cardiovascular disorders,</p><p>such as myocardial infarction, congestive heart failure, atrial fibrillation, atherosclerosis, and related</p><p>risk factors [86,87].</p><p>In a cross-sectional study [67], it was shown that there is a significant impact of sarcopenia on the</p><p>occurrence of stroke in elderly individuals. In another study with 316 elderly patients with stroke,</p><p>Nozoe et al. [88] showed that the appearance of pre-stroke sarcopenia is an independent predictor of</p><p>moderate to severe stroke.</p><p>Anaszewicz et al. [89] in a cohort study showed that patients with atrial fibrillation had a higher</p><p>body mass index, larger waist circumference and visceral adiposity, higher values for fat and fat-free</p><p>mass, and reduced percentage of skeletal muscle mass, indicating a higher prevalence of obesity and</p><p>sarcopenia in these patients.</p><p>An official website of the United States government</p><p>NCBI Literature Resources MeSH PMC Bookshelf Disclaimer</p><p>The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of</p><p>these marks is strictly prohibited.</p><p>FOLLOW NCBI</p><p>Here's how you know</p><p>Advanced Create alert Create RSS User Guide</p><p>myokine Search</p><p>Save Email Send to</p><p>1,945 results Page 1 of 195</p><p>First Prev Page 1 of 195 Next Last</p><p>Searches related to "myokine"</p><p>muscle myokine</p><p>myokine review</p><p>exercise myokine</p><p>il-6 myokine</p><p>myokine exercise</p><p>myokine muscle</p><p>myokine irisin</p><p>myokine diabetes</p><p>skeletal muscle myokine</p><p>myokine secretion</p><p>Did you mean myokiny (1 results)?</p><p>1</p><p>Muscle-to-tumor crosstalk: The effect of exercise-induced myokine on cancer</p><p>progression.</p><p>Huang Q, Wu M, Wu X, Zhang Y, Xia Y.</p><p>Biochim Biophys Acta Rev Cancer. 2022 Sep;1877(5):188761. doi: 10.1016/j.bbcan.2022.188761.</p><p>Epub 2022 Jul 16.</p><p>PMID: 35850277 Review.</p><p>In recent decades, skeletal muscles have been considered endocrine organs, exerting their</p><p>biological functions via the endocrine, autocrine, and paracrine systems by secreting various types</p><p>of myokines. The amount of myokines secreted varies depending on the intensi …</p><p>Cite</p><p>Share</p><p>2</p><p>Multiple Roles in Neuroprotection for the Exercise Derived Myokine Irisin.</p><p>Jodeiri Farshbaf M, Alviña K.</p><p>Front Aging Neurosci. 2021 Apr 16;13:649929. doi: 10.3389/fnagi.2021.649929. eCollection 2021.</p><p>PMID: 33935687 Free PMC article. Review.</p><p>Such effects are thought to be mediated (at least in part) by myokines, a collection of cytokines</p><p>and other small proteins released from skeletal muscles. As an endocrine organ, skeletal muscle</p><p>synthesizes and secretes a wide range of myokines which contribute to di …</p><p>Cite</p><p>Share</p><p>3</p><p>Muscle-Organ Crosstalk: The Emerging Roles of Myokines.</p><p>Severinsen MCK, Pedersen BK.</p><p>Endocr Rev. 2020 Aug 1;41(4):594-609. doi: 10.1210/endrev/bnaa016.</p><p>PMID: 32393961 Free PMC article. Review.</p><p>Although only few myokines have been allocated to a specific function in humans, it has been</p><p>identified that the biological roles of myokines include effects on, for example, cognition, lipid and</p><p>glucose metabolism, browning of white fat, bone formation, endothelial …</p><p>Cite</p><p>Share</p><p>4</p><p>Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin</p><p>Response and Metabolic Homeostasis.</p><p>Wu HK, Zhang Y, Cao CM, Hu X, Fang M, Yao Y, Jin L, Chen G, Jiang P, Zhang S, Song R, Peng W, Liu</p><p>F, Guo J, Tang L, He Y, Shan D, Huang J, Zhou Z, Wang DW, Lv F, Xiao RP.</p><p>Circulation. 2019 Feb 12;139(7):901-914. doi: 10.1161/CIRCULATIONAHA.118.037216.</p><p>PMID: 30586741</p><p>Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that</p><p>regulate systemic metabolic processes. We hypothesize that MG53 may act as a</p><p>myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic …</p><p>Cite</p><p>Share</p><p>5</p><p>Myokine, a key cytokine for physical exercise to alleviate sarcopenic obesity.</p><p>Zhang L, Lv J, Wang C, Ren Y, Yong M.</p><p>Mol Biol Rep. 2023 Mar;50(3):2723-2734. doi: 10.1007/s11033-022-07821-3. Epub 2022 Dec 26.</p><p>PMID: 36571655 Review.</p><p>Skeletal muscle has a robust endocrine function as a powerful organ and can secrete and release</p><p>cytokines or polypeptides known as myokines. These myokines have significant regulatory effects</p><p>on signal transduction in skeletal muscle and the metabolism of peripheral …</p><p>Cite</p><p>Share</p><p>6</p><p>Myokine-mediated exercise effects: the role of myokine meteorin-like hormone</p><p>(Metrnl).</p><p>Alizadeh H.</p><p>Growth Factors. 2021 Feb-Jul;39(1-6):71-78. doi: 10.1080/08977194.2022.2032689. Epub 2022 Feb</p><p>8.</p><p>PMID: 35133923 Review.</p><p>Exercise-induced Metrnl</p><p>actions are increased fat oxidation in both skeletal muscle and adipose</p><p>tissue, the control of inflammation in adipose tissue (metainflammation), and the regulation of</p><p>muscle regeneration. Based on the current knowledge, Metrnl as a myokine can esta …</p><p>Cite</p><p>Share</p><p>7</p><p>A new paradigm in sarcopenia: Cognitive impairment caused by imbalanced</p><p>myokine secretion and vascular dysfunction.</p><p>Jo D, Yoon G, Kim OY, Song J.</p><p>Biomed Pharmacother. 2022 Mar;147:112636. doi: 10.1016/j.biopha.2022.112636. Epub 2022 Jan 17.</p><p>PMID: 35051857 Free article. Review.</p><p>Many researchers suggested that the prevalence of sarcopenia is associated with vascular disorder,</p><p>such as atherosclerosis and alteration of intracellular mechanisms caused by changes in myokine</p><p>secretion. We herein review the emerging evidence on the strong link between c …</p><p>Cite</p><p>Share</p><p>8</p><p>Gut microbiota and regulation of myokine-adipokine function.</p><p>Suriano F, Van Hul M, Cani PD.</p><p>Curr Opin Pharmacol. 2020 Jun;52:9-17. doi: 10.1016/j.coph.2020.03.006. Epub 2020 May 7.</p><p>PMID: 32388413 Free article. Review.</p><p>Both skeletal muscle and adipose tissue are considered as endocrine organs due to their ability to</p><p>produce and secrete several bioactive peptides (e.g. myokines and adipokines). Those bioactive</p><p>molecules are well known for their capacity to influence whole-body homeostasis …</p><p>Cite</p><p>Share</p><p>9</p><p>Myokine Expression and Tumor-Suppressive Effect of Serum after 12 wk of</p><p>Exercise in Prostate Cancer Patients on ADT.</p><p>Kim JS, Wilson RL, Taaffe DR, Galvão DA, Gray E, Newton RU.</p><p>Med Sci Sports Exerc. 2022 Feb 1;54(2):197-205. doi: 10.1249/MSS.0000000000002783.</p><p>PMID: 34559721 Free PMC article. Clinical Trial.</p><p>PURPOSE: Although several mechanisms have been proposed for the tumor-suppressive effect of</p><p>exercise, little attention has been given to myokines, even though skeletal muscle is heavily</p><p>recruited during exercise resulting in myokine surges. We measured resting serum …</p><p>Cite</p><p>Share</p><p>10</p><p>Dipeptidyl Peptidase IV as a Muscle Myokine.</p><p>Kluess HA.</p><p>Front Physiol. 2020 Mar 3;11:148. doi: 10.3389/fphys.2020.00148. eCollection 2020.</p><p>PMID: 32194435 Free PMC article. Review.</p><p>Recent work suggests that skeletal muscle releases DPP-IV as a myokine and participates in control</p><p>of muscle blood flow. However, few of the functions of DPP-IV as a myokine have been investigated</p><p>to date and there is a poor understanding about what causes DPP-IV to …</p><p>Cite</p><p>Share</p><p>Show more results1,945 results</p><p>Connect with NLM</p><p>National Library of</p><p>Medicine</p><p>8600 Rockville Pike</p><p>Bethesda, MD 20894</p><p>Web Policies</p><p>FOIA</p><p>HHS Vulnerability</p><p>Disclosure</p><p>Help</p><p>Accessibility</p><p>Careers</p><p>NLM NIH HHS USA.gov</p><p>MY NCBI FILTERS</p><p>TEXT AVAILABILITY</p><p>ARTICLE ATTRIBUTE</p><p>ARTICLE TYPE</p><p>PUBLICATION DATE</p><p>Additional filters</p><p>Reset all filters</p><p>RESULTS BY YEAR</p><p>Abstract</p><p>Free full text</p><p>Full text</p><p>Associated data</p><p>Books and Documents</p><p>Clinical Trial</p><p>Meta-Analysis</p><p>Randomized Controlled</p><p>Trial</p><p>Review</p><p>Systematic Review</p><p>1 year</p><p>5 years</p><p>10 years</p><p>Custom Range</p><p>Expand/collapse timeline</p><p>20232003</p><p>Sort by: Best match Display options</p><p>Log in</p><p>NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | AUGUST 2012 | 457</p><p>The Centre of</p><p>Inflammation and</p><p>Metabolism,</p><p>Department of</p><p>Infectious Diseases</p><p>and CMRC,</p><p>Rigshospitalet, Section</p><p>7641, Faculty of Health</p><p>Sciences, University</p><p>of Copenhagen,</p><p>Blegdamsvej 9,</p><p>DK-2100, Copenhagen,</p><p>Denmark</p><p>(B. K. Pedersen).</p><p>Cellular and Molecular</p><p>Metabolism Laboratory,</p><p>Baker IDI Heart and</p><p>Diabetes Institute,</p><p>75 Commercial Road,</p><p>Melbourne, VIC 3004,</p><p>Australia</p><p>(M. A. Febbraio).</p><p>Correspondence to:</p><p>B. K. Pedersen</p><p>bkp@rh.dk</p><p>Muscles, exercise and obesity: skeletal muscle</p><p>as a secretory organ</p><p>Bente K. Pedersen and Mark A. Febbraio</p><p>Abstract | During the past decade, skeletal muscle has been identified as a secretory organ. Accordingly, we</p><p>have suggested that cytokines and other peptides that are produced, expressed and released by muscle</p><p>fibres and exert either autocrine, paracrine or endocrine effects should be classified as myokines. The finding</p><p>that the muscle secretome consists of several hundred secreted peptides provides a conceptual basis and</p><p>a whole new paradigm for understanding how muscles communicate with other organs, such as adipose</p><p>tissue, liver, pancreas, bones and brain. However, some myokines exert their effects within the muscle itself.</p><p>Thus, myostatin, LIF, IL-6 and IL-7 are involved in muscle hypertrophy and myogenesis, whereas BDNF and IL-6</p><p>are involved in AMPK-mediated fat oxidation. IL-6 also appears to have systemic effects on the liver, adipose</p><p>tissue and the immune system, and mediates crosstalk between intestinal L cells and pancreatic islets. Other</p><p>myokines include the osteogenic factors IGF-1 and FGF-2; FSTL-1, which improves the endothelial function of the</p><p>vascular system; and the PGC-1α-dependent myokine irisin, which drives brown-fat-like development. Studies</p><p>in the past few years suggest the existence of yet unidentified factors, secreted from muscle cells, which may</p><p>influence cancer cell growth and pancreas function. Many proteins produced by skeletal muscle are dependent</p><p>upon contraction; therefore, physical inactivity probably leads to an altered myokine response, which could</p><p>provide a potential mechanism for the association between sedentary behaviour and many chronic diseases.</p><p>Pedersen, B. K. & Febbraio, M. A. Nat. Rev. Endocrinol. 8, 457–465 (2012); published online 3 April 2012; doi:10.1038/nrendo.2012.49</p><p>Introduction</p><p>The views on hormonal regulation of metabolism in</p><p>health and disease have markedly changed over the</p><p>past 20 years, principally owing to extensive research</p><p>into adipose tissue. Initially considered an inert storage</p><p>compartment for triglycerides, pioneering work in the</p><p>mid 1980s demonstrated that adipocytes are an abun-</p><p>dant source of a specific secretory protein called com-</p><p>plement factor D or adipsin.1 A little over a decade ago,</p><p>in a landmark finding, Zhang et al.2 identified leptin as</p><p>a fat-cell-specific secretory factor—lacking in the obese</p><p>ob/ob mouse—that mediates a canonical hormonal</p><p>signal between adipose tissue and the brain. Since then,</p><p>adiponectin, resistin, nicotinamide phosphoribosyl-</p><p>transferase (also known as visfatin) and retinol-binding</p><p>protein 4 have joined the growing list of adipokines.3</p><p>Although adipokines have been the focus of much</p><p>research in terms of their role as circulatory factors with</p><p>effects on metabolically active tissue, it should be noted</p><p>that during contractions, muscle cells undergo one of the</p><p>most marked alterations to cellular quiescence in physio-</p><p>logy and indeed pathophysiology. In addition, exercise</p><p>influences the metabolism and function of several organs.</p><p>Muscles, therefore, could represent an important source of</p><p>se cretory molecules with either local or en docrine effects.</p><p>Apart from adiponectin,4 most of the factors that</p><p>are produced by adipocytes are proinflammatory—for</p><p>example, TNF, CCL2 and PAI-1—and are potentially</p><p>harmful with regard to the development of obesity-</p><p>induced metabolic and cardiovascular diseases. This</p><p>understanding raises the important question of which</p><p>tissue or tissues could be protective and provide a</p><p>counter balance to the proinflammatory factors that are</p><p>produced by adipocytes.</p><p>Even short periods of physical inactivity are associ-</p><p>ated with metabolic changes, including decreased insulin</p><p>sensitivity, attenuation of postprandial lipid metabo-</p><p>lism, loss of muscle mass and accumulation of visceral</p><p>adipose tissue.5,6 Such abnormalities probably represent</p><p>a link between reduced exercise and increased risks of</p><p>the progression of chronic disorders and premature</p><p>mor tality.7 Physical inactivity increases the risk of type 2</p><p>diabetes mellitus (T2DM),8 cardiovascular diseases,9</p><p>colon cancer,10 postmenopausal breast cancer11 and</p><p>osteo porosis.12 A reasonable suggestion is that skeletal</p><p>muscle might mediate some of the well-established pro-</p><p>tective effects of exercise via secretion of proteins</p><p>that</p><p>could counteract the harmful effects of proinflammatory</p><p>ad ipokines (Figure 1).</p><p>The idea that muscle cells might produce and release</p><p>a humoral factor dates back many years before the iden-</p><p>tification of adipose tissue as an endocrine organ. For</p><p>nearly half a century, researchers had hypothesized that</p><p>skeletal muscle cells possess a ‘humoral’ factor that is</p><p>released in response to increased glucose demand during</p><p>con traction.13 To date, owing to lack of more precise</p><p>Competing interests</p><p>The authors declare no competing interests.</p><p>REVIEWS</p><p>© 2012 Macmillan Publishers Limited. All rights reserved</p><p>NATURE REVIEWS | ENDOCRINOLOGY VOLUME 8 | AUGUST 2012 | 459</p><p>IL-6</p><p>The cytokine IL-6 was the first myokine found to be</p><p>secreted into the bloodstream in response to muscle</p><p>contractions.23 The cytokine was serendipitously dis-</p><p>covered as a myokine because of the observation that its</p><p>levels increased in an exponential fashion proportional</p><p>to the length of exercise and the amount of muscle mass</p><p>engaged in the exercise. Thus, plasma IL-6 levels can</p><p>increase up to 100-fold in response to exercise, although</p><p>less dramatic increases are more frequent.37 IL-6 is</p><p>expressed by human myoblasts,38,39 human cultured myo-</p><p>tubes,40 growing murine myofibres and associated muscle</p><p>stem cells (satel lite cells).41 In addition, IL-6 is released</p><p>from human primary muscle cell cultures from healthy</p><p>indivi duals and from patients with T2DM.42,43</p><p>Interestingly, the increase in IL-6 levels in the circula-</p><p>tion occurs during exercise without any sign of muscle</p><p>damage.37 Until the beginning of this millennium, it was</p><p>commonly thought that the increase in IL-6 levels during</p><p>exercise was a consequence of an immune response</p><p>owing to local damage in the working muscles,44 and</p><p>macro phages were hypothesized to be responsible for</p><p>this increase.45 However, the IL6 mRNA level in mono-</p><p>cytes does not increase as a result of exercise.46 This</p><p>finding was confirmed at the protein level.47,48 Today,</p><p>muscle cells are known to be the dominant source of IL-6</p><p>production during exercise. Furthermore, the hepatos-</p><p>planchnic viscera remove IL-6 from the circulation in</p><p>humans during exercise.49 The removal of IL-6 by the</p><p>liver could constitute a mechanism that limits the nega-</p><p>tive metabolic effects of chronically elevated levels of</p><p>circulating IL-6.</p><p>Several pieces of evidence support the notion that IL-6</p><p>is produced by muscle cells during exercise. The nuclear</p><p>transcription rate for IL-6 and IL6 mRNA levels increase</p><p>rapidly and markedly within 30 min of the onset of exer-</p><p>cise.50,51 which suggests that a factor associated with con-</p><p>traction is involved in the regulation of IL-6 transcription</p><p>within the nuclei of muscle cells. Further evidence that</p><p>contracting muscle fibres are themselves a source of IL6</p><p>mRNA and protein has been gained from analysis of</p><p>biopsy samples from the human vastus lateral is muscle</p><p>using in situ hybridization and immunohistochemistry</p><p>techniques.52 Microdialysis studies suggest that the con-</p><p>centration of IL-6 within the contracting skeletal muscle</p><p>could be fivefold to 100-fold higher than the levels</p><p>found in the circulation and supports the idea that IL-6</p><p>accumulates within muscle fibres as well as in the inter-</p><p>stitium during and following exercise.53 The simulta neous</p><p>measure ment of arteriovenous IL-6 concentrations and</p><p>blood flow across an exercising leg has demonstrated that</p><p>large amounts of IL-6 are also released into the circulation</p><p>from the exercising muscle.54</p><p>Human skeletal muscle is unique in that it can produce</p><p>IL-6 during contraction in a strictly TNF-independent</p><p>fashion.40 This finding suggests that muscular IL-6</p><p>has a role in metabolism rather than in inflammation.</p><p>In support of this hypothesis, both intramuscular IL6</p><p>mRNA expression55 and IL-6 protein release56 are mark-</p><p>edly enhanced when intramuscular glycogen levels</p><p>are low, which suggests that IL-6 works as an energy</p><p>sensor.57–60 This idea is supported by numerous studies</p><p>showing that glucose ingestion during exercise attenu-</p><p>ates the exercise-induced increase in plasma IL-623 and</p><p>inhibits the IL-6 release from contracting skeletal muscle</p><p>in humans.23,61</p><p>Skeletal muscle is a tissue that is capable of altering</p><p>the type and amount of protein in response to regular</p><p>exercise. Exercise-induced adaptation in skeletal muscle</p><p>increases pre-exercise skeletal muscle glycogen content,</p><p>enhances activity of key enzymes involved in β-oxidation,</p><p>increases sensitivity of adipose tissue to epinephrine-</p><p>stimulated lipolysis, and increases oxidation of intra-</p><p>muscular triglycerides. As a consequence, the trained</p><p>skeletal muscle can utilize fat as a substrate and is less</p><p>dependent on plasma glucose and muscle glycogen as</p><p>substrates during exercise.23,62 Several epidemiological</p><p>studies have reported a negative association between the</p><p>amount of regular physical activity and resting plasma</p><p>IL-6 levels: the more physical activity, the lower the basal</p><p>plasma IL-6 level.37 By contrast, high basal plasma levels</p><p>of IL-6 are closely associated with physical inactivity and</p><p>the metabolic syndrome. Moreover, basal levels of IL-6</p><p>are reduced after endurance training.37 In addition, the</p><p>exercise-induced increase in plasma IL-6 and muscular</p><p>IL6 mRNA levels is diminished by endurance training.63</p><p>Interestingly, although resting plasma IL-6 levels are</p><p>downregulated by endurance training, the resting mus-</p><p>cular expression of IL-6Rα is upregulated. In response</p><p>to endurance training, the basal IL6Rα mRNA content</p><p>in muscle is increased by ~100%.55 Thus, with exercise</p><p>IL-6</p><p>IL-6</p><p>IL-6</p><p>IL-6</p><p>BDNF</p><p>IGF-1</p><p>FGF-2</p><p>Lipolysis</p><p>Lipolysis</p><p>Hypertrophy</p><p>Glucose</p><p>uptake</p><p>Fat oxidation</p><p>IL-8?</p><p>CXCL-1?</p><p>Follistatin-related</p><p>protein 1</p><p>IL-6</p><p>Hepatic glucose</p><p>production</p><p>during exercise</p><p>Unknown</p><p>exercise</p><p>stimulus</p><p>Follistatin</p><p>Myostatin</p><p>LIF</p><p>IL-4</p><p>IL-6</p><p>IL-7</p><p>IL-15 Hepatic CXCL-1</p><p>production</p><p>Promotes endothelial</p><p>function and</p><p>revascularization</p><p>IL-6</p><p>Angiogenesis</p><p>FGF-21</p><p>AMPK</p><p>Irisin</p><p>UCP-1</p><p>Insulin secretion</p><p>via GLP-1</p><p>Figure 2 | Skeletal muscle is a secretory organ. LIF, IL-4, IL-6, IL-7 and IL-15</p><p>promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and exercise</p><p>provokes the release of a myostatin inhibitor, follistatin, from the liver. BDNF and</p><p>IL-6 are involved in AMPK-mediated fat oxidation and IL-6 enhances insulin-</p><p>stimulated glucose uptake. IL-6 appears to have systemic effects on the liver and</p><p>adipose tissue and increases insulin secretion via upregulation of GLP-1. IGF-1</p><p>and FGF-2 are involved in bone formation, and follistatin-related protein 1 improves</p><p>endothelial function and revascularization of ischaemic vessels. Irisin has a role in</p><p>‘browning’ of white adipose tissue.</p><p>REVIEWS</p><p>© 2012 Macmillan Publishers Limited. All rights reserved</p><p>462 | AUGUST 2012 | VOLUME 8 www.nature.com/nrendo</p><p>by proteome analysis in medium conditioned by cultured</p><p>human myotubes.114 Reverse transcription PCR analy-</p><p>ses showed that 15 of the secreted muscle proteins had</p><p>markedly enhanced mRNA expression in the vastus lat-</p><p>eralis and/or trapezius muscles after 11 weeks of strength</p><p>t raining among healthy volunteers.</p><p>Myokines: clinical aspects</p><p>Many of the myokines identified exert their effects within</p><p>the muscle itself. Thus, myostatin, LIF, IL-4, IL-6, IL-7</p><p>and IL-15 are involved in the regulation of muscle hyper-</p><p>trophy and myogenesis. BDNF and IL-6 are involved in</p><p>AMPK-mediated fat oxidation and IL-8 (or CXCL-1)</p><p>might be involved in mediating training-induced angio-</p><p>genesis. However, IL-6 also appears to mediate systemic</p><p>effects, including effects on the liver, adipose tissue and</p><p>the immune system. Follistatin-related protein 1 has</p><p>been identified to play a role in promoting endothelial</p><p>cell function and revascularization under conditions</p><p>of ischaemic stress, and IGF-1 and FGF-2 appear to be</p><p>involved in muscle–bone crosstalk.</p><p>The myokine field is new and, to date, most of the</p><p>human studies have focused</p><p>on the biological role of</p><p>IL-6. The finding that muscle-derived IL-6 has several</p><p>beneficial metabolic effects suggests that it has a role in</p><p>the association between a physically inactive lifestyle</p><p>and an increased risk of chronic diseases. Sadagurski</p><p>and colleagues have demonstrated that transgenic mice</p><p>with sustained elevated circulating levels of human IL-6</p><p>display enhanced central leptin action and improved</p><p>nutrient homeostasis that leads to protection from diet-</p><p>induced obesity.115 In addition, Wunderlich et al.116 have</p><p>shown that IL-6 signalling is required for normal liver</p><p>metabolism in mice. Of note, ciliary neurotrophic factor</p><p>is a member of the IL-6 family of cytokines and also</p><p>improves metabolic homeostasis in mice when insulin</p><p>resistance is induced either from a high-fat diet70 or lipid</p><p>infusion.117 Interestingly, a ciliary neurotrophic factor</p><p>variant, axokine, was in clinical trials for the treatment</p><p>of T2DM, but failed to be approved owing to a lack of</p><p>a neutralizing effect of the antibody.118 Nonetheless,</p><p>the finding that exercise has multiple beneficial effects,</p><p>which may be mediated by myokines, suggests that there</p><p>might be therapeutic potential in myokine research.</p><p>Apart from the effects of myokines on peripheral</p><p>insulin sensitivity via the activation of AMPK, evidence</p><p>is emerging that myokines might also play a major part</p><p>in pancreatic β-cell metabolism and insulin secretion.</p><p>Bouzakri et al. showed that human myotubes express</p><p>and release a different panel of myokines depending on</p><p>their insulin sensitivity, with each panel exerting differ-</p><p>ential effects on β cells. These preliminary data suggest</p><p>a new route of communication between skeletal muscle</p><p>and β cells, which is modulated by insulin resistance.119</p><p>Moreover, Ellingsgaard and colleagues showed that</p><p>whereas exercise increased glucose tolerance in normal</p><p>mice, this phenomenon did not occur in mice with global</p><p>IL-6 deficiency.120 Using several elegant models, the</p><p>researchers were able to show that the exercise-induced</p><p>GLP-1 response was dependent upon muscle-derived</p><p>IL-6. Hence, IL-6 mediates crosstalk between two dif-</p><p>ferent insulin-sensitive tissues, the gut and pancreatic</p><p>islets, in order to adapt to changes in insulin demand by</p><p>increasing GLP-1 secretion.</p><p>Epidemiological studies suggest an increased risk</p><p>of breast cancer in women with a sedentary lifestyle,</p><p>whereas regular physical activity protects against the</p><p>Physical inactivity</p><p>Loss of muscle mass and abdominal adiposity</p><p>Macrophage in!ltration of visceral adipose tissue</p><p>Chronic systemic in"ammation</p><p>Insulin resistance, atherosclerosis,</p><p>tumour growth, impaired bone formation</p><p>Type 2 diabetes mellitus, cardiovascular diseases,</p><p>cancer, osteoporosis</p><p>Figure 3 | Links between physical inactivity and disease</p><p>development. Loss of muscle mass and accumulation</p><p>of visceral adipose tissue are general consequences of</p><p>physical inactivity. Abdominal adiposity stimulates</p><p>macrophage infiltration of adipose tissue, whereby a</p><p>network of inflammatory pathways is activated.</p><p>Inflammation promotes development of insulin resistance,</p><p>atherosclerosis, neurodegeneration, tumour growth and</p><p>impaired bone formation and, consequently, the</p><p>development of a myriad of chronic diseases. During</p><p>physical activity, muscles release myokines, which</p><p>stimulate muscle growth and hypertrophy, increase fat</p><p>oxidation, enhance insulin sensitivity and induce anti-</p><p>inflammatory actions.</p><p>Myokines</p><p>Physical activity</p><p>Decreased risk of chronic diseases and premature mortality</p><p>Muscle hypertrophy (myostatin, LIF, IL-4, IL-6, IL-7, IL-15)</p><p>Adipose tissue oxidation (IL-6, BDNF)</p><p>Insulin sensitivity (IL-6)</p><p>Osteogenesis (IGF-1, FGF-2)</p><p>Anti-in!ammation (IL-6)</p><p>Anti-tumour defence (unidenti"ed secreted factor(s))</p><p>Pancreas function (unidenti"ed secreted factor(s))</p><p>Browning of fat (Irisin)</p><p>Figure 4 | The finding that muscle produces and releases</p><p>myokines provides a conceptual basis for understanding</p><p>some of the molecular mechanisms that link physical</p><p>activity to protection against premature mortality.</p><p>REVIEWS</p><p>© 2012 Macmillan Publishers Limited. All rights reserved</p><p>fphys-12-709807 August 6, 2021 Time: 14:57 # 1</p><p>REVIEW</p><p>published: 12 August 2021</p><p>doi: 10.3389/fphys.2021.709807</p><p>Edited by:</p><p>Domenico Di Raimondo,</p><p>Università degli Studi di Palermo, Italy</p><p>Reviewed by:</p><p>Vanessa Azevedo Voltarelli,</p><p>Hospital Sirio Libanes, Brazil</p><p>Tibor Hortobagyi,</p><p>University Medical Center Groningen,</p><p>Netherlands</p><p>*Correspondence:</p><p>Christoph Handschin</p><p>christoph.handschin@unibas.ch</p><p>Specialty section:</p><p>This article was submitted to</p><p>Exercise Physiology,</p><p>a section of the journal</p><p>Frontiers in Physiology</p><p>Received: 14 May 2021</p><p>Accepted: 23 July 2021</p><p>Published: 12 August 2021</p><p>Citation:</p><p>Leuchtmann AB, Adak V, Dilbaz S</p><p>and Handschin C (2021) The Role</p><p>of the Skeletal Muscle Secretome</p><p>in Mediating Endurance</p><p>and Resistance Training Adaptations.</p><p>Front. Physiol. 12:709807.</p><p>doi: 10.3389/fphys.2021.709807</p><p>The Role of the Skeletal Muscle</p><p>Secretome in Mediating Endurance</p><p>and Resistance Training Adaptations</p><p>Aurel B. Leuchtmann, Volkan Adak, Sedat Dilbaz and Christoph Handschin*</p><p>Biozentrum, University of Basel, Basel, Switzerland</p><p>Exercise, in the form of endurance or resistance training, leads to specific molecular</p><p>and cellular adaptions not only in skeletal muscles, but also in many other organs</p><p>such as the brain, liver, fat or bone. In addition to direct effects of exercise on these</p><p>organs, the production and release of a plethora of different signaling molecules</p><p>from skeletal muscle are a centerpiece of systemic plasticity. Most studies have</p><p>so far focused on the regulation and function of such myokines in acute exercise</p><p>bouts. In contrast, the secretome of long-term training adaptation remains less</p><p>well understood, and the contribution of non-myokine factors, including metabolites,</p><p>enzymes, microRNAs or mitochondrial DNA transported in extracellular vesicles or by</p><p>other means, is underappreciated. In this review, we therefore provide an overview on</p><p>the current knowledge of endurance and resistance exercise-induced factors of the</p><p>skeletal muscle secretome that mediate muscular and systemic adaptations to long-</p><p>term training. Targeting these factors and leveraging their functions could not only have</p><p>broad implications for athletic performance, but also for the prevention and therapy in</p><p>diseased and elderly populations.</p><p>Keywords: skeletal muscle, exercise, myokines, PGC-1alpha, endurance training, resistance training, secretome</p><p>INTRODUCTION</p><p>Exercise, in its various forms, provides an array of physiological stimuli that evokes metabolic</p><p>and molecular perturbations in skeletal muscle as well as many other organ systems. Training</p><p>adaptations are structural and functional changes resulting from repeated exposure to these</p><p>exercise-induced stimuli, leading to improved physiological capacity and decreased risk for</p><p>morbidity and mortality (Egan and Zierath, 2013). The detailed molecular processes induced by</p><p>di�erent exercise stimuli are, however, still poorly characterized. In particular, it is incompletely</p><p>understood how the signals induced by acute exercise bouts translate into specific adaptations</p><p>following long-term training (Sanford et al., 2020). A sound understanding of the mechanisms</p><p>underlying the adaptation to exercise training and the identification of molecular e�ectors of</p><p>the adaptive response is essential—not only for individuals with athletic ambitions, but also to</p><p>infer potential clinical implications and to develop novel therapeutic avenues for geriatric and</p><p>diseased populations.</p><p>Endurance and resistance exercise are the two extremes of a broad continuum of exercise</p><p>modalities and elicit distinct but also overlapping training responses (Egan and Zierath, 2013).</p><p>Acutely, both endurance and resistance exercise trigger the systemic release of a plethora of</p><p>Frontiers in Physiology | www.frontiersin.org 1 August 2021 | Volume 12 | Article 709807</p><p>fphys-12-709807 August</p><p>6, 2021 Time: 14:57 # 9</p><p>Leuchtmann et al. Myokines in Exercise Training Adaptation</p><p>FIGURE 1 | Schematic overview of examples of the endurance (left) and resistance (right) exercise-induced muscle secretome and its auto-, para-, and endocrine</p><p>actions involved in training adaptation. See text for details. Abbreviations: AMPK, AMP-dependent protein kinase; Apelin, APJ Endogenous Ligand; BAIBA,</p><p>b-aminoisobutyric acid; BDNF, Brain-derived neurotrophic factor; BNP, B-type or brain natriuretic peptide; EC, endothelial cell; ECM, Extracellular matrix; GDF3,</p><p>macrophage-derived growth differentiation factor 3; GDNF, glial cell line-derived neurotrophic factor, IGF-1, Insulin-like growth factor-1; ILC2, innate lymphoid cells</p><p>type 2; IL-6, Interleukin-6; IL-8, Interleukin-8; IL-13, Interleukin-13; LIF, Leukemia inhibitory factor; MOTS-c, mitochondrial ORF of the 12S ribosomal RNA type-c;</p><p>MMP2, Matrix metalloproteinase-2; mTORC1, mammalian target of rapamycin complex 1; NMJ, Neuromuscular junction; PGC-1a, peroxisome proliferator-activated</p><p>receptor g coactivator 1a; SPARC, Secreted protein acidic and rich in cysteine; SPP-1, secreted phosphoprotein 1; TF, transcription factor; VEGF, Vascular</p><p>endothelial growth factor; YAP1, Yes-associated protein 1.</p><p>SCs, was enhanced upon an acute bout of resistance exercise</p><p>(Grubb et al., 2014). However, whether SC activating IGF-1 is</p><p>myofiber-derived in this context is di�cult to estimate, as other</p><p>cell types are also likely to be involved. Besides SCs themselves as</p><p>a potential source, IGF-1 derived from monocytes/macrophages</p><p>is known to be crucial during ECM remodeling and regeneration</p><p>from muscle injury (Tonkin et al., 2015). Another layer of</p><p>complexity in the regulation of IGF-1 signaling in response to</p><p>exercise is added by the array of IGF-1 binding proteins that can</p><p>either inhibit or promote IGF-1 bioavailability and physiological</p><p>activity (Allard and Duan, 2018).</p><p>Finally, as IGF-1 is positively associated with bone</p><p>mineralization (Breen et al., 2011), IGF-1 could also be</p><p>involved in muscle-bone crosstalk by acting on IGF-1 receptors</p><p>Frontiers in Physiology | www.frontiersin.org 9 August 2021 | Volume 12 | Article 709807</p><p>International Journal of</p><p>Molecular Sciences</p><p>Review</p><p>Physical Exercise-Induced Myokines in Neurodegenerative Diseases</p><p>Banseok Lee</p><p>1,†</p><p>, Myeongcheol Shin</p><p>1,†</p><p>, Youngjae Park</p><p>1</p><p>, So-Yoon Won</p><p>1,2,</p><p>* and Kyoung Sang Cho</p><p>1,2,</p><p>*</p><p>!"#!$%&'(!</p><p>!"#$%&'</p><p>Citation: Lee, B.; Shin, M.; Park, Y.;</p><p>Won, S.-Y.; Cho, K.S. Physical</p><p>Exercise-Induced Myokines in</p><p>Neurodegenerative Diseases. Int. J.</p><p>Mol. Sci. 2021, 22, 5795. https://</p><p>doi.org/10.3390/ijms22115795</p><p>Academic Editor: Tomasz Brzozowski</p><p>Received: 19 April 2021</p><p>Accepted: 25 May 2021</p><p>Published: 28 May 2021</p><p>Publisher’s Note: MDPI stays neutral</p><p>with regard to jurisdictional claims in</p><p>published maps and institutional affil-</p><p>iations.</p><p>Copyright: © 2021 by the authors.</p><p>Licensee MDPI, Basel, Switzerland.</p><p>This article is an open access article</p><p>distributed under the terms and</p><p>conditions of the Creative Commons</p><p>Attribution (CC BY) license (https://</p><p>creativecommons.org/licenses/by/</p><p>4.0/).</p><p>1 Department of Biological Sciences, Konkuk University, Seoul 05029, Korea; jitcouk@konkuk.ac.kr (B.L.);</p><p>shmych1022@konkuk.ac.kr (M.S.); pyj7377@konkuk.ac.kr (Y.P.)</p><p>2 Korea Hemp Institute, Konkuk University, Seoul 05029, Korea</p><p>* Correspondence: sywon@konkuk.ac.kr (S.-Y.W.); kscho@konkuk.ac.kr (K.S.C.); Tel.: +82-10-3688-5474</p><p>(S.-Y.W.); Tel.: +82-2-450-3424 (K.S.C.)</p><p>† The authors contributed equally to this work.</p><p>Abstract: Neurodegenerative diseases (NDs), such as Alzheimer’s disease (AD), Parkinson’s disease</p><p>(PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders character-</p><p>ized by progressive degeneration of the nervous system. Currently, there is no disease-modifying</p><p>treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models</p><p>over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue com-</p><p>munication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is</p><p>thought to be an important underlying mechanism for the advantages. Here, we reviewed studies</p><p>about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could</p><p>exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival,</p><p>neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies</p><p>on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which</p><p>there are no adequate treatments nowadays. To date, only a few myokines have been investigated</p><p>for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore,</p><p>future studies are needed to discover more myokines and test their effects on NDs.</p><p>Keywords: Alzheimer’s disease; amyotrophic lateral sclerosis; exercise; Huntington’s disease;</p><p>muscle–brain axis; myokines; neurodegenerative diseases; Parkinson’s disease</p><p>1. Introduction</p><p>Neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s</p><p>disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are</p><p>characterized by progressive loss of neurons and accumulation of abnormal protein aggre-</p><p>gates [1]. They are accompanied by cognitive impairments, memory loss, and locomotor</p><p>deficits and share several fundamental processes, including cell survival, neurogenesis,</p><p>neuroinflammation, proteostasis, oxidative stress, and protein modification [2–7]. The</p><p>pathological hallmark of each ND contains an abnormal aggregation of different proteins:</p><p>amyloid-� (A�) and tau in AD, ↵-synuclein in PD, huntingtin in HD, and several proteins</p><p>including Tar DNA-binding protein of 43 kDa (TDP-43) and mutant superoxide dismutase</p><p>1 (SOD1) in ALS [8]. Pathological deposition of these proteins in neurons takes place long</p><p>before psychological symptoms of each ND appear, and substances that can block their</p><p>abnormal aggregation are expected to be used as preventive or therapeutic agents for</p><p>NDs [9–13].</p><p>Results of numerous studies conducted on human and animal models over the past</p><p>decades have shown that exercise has beneficial effects not only on physical health, but</p><p>also on neuronal functions, resulting in improved learning and memory, inhibition of</p><p>neurodegeneration, and reduction of depression [14]. Exercise can increase brain volume or</p><p>connectivity by enhancing neurogenesis and synaptic plasticity and changing metabolism</p><p>and vascular function [14,15]. Beneficial effects of exercise on brain health are thought to be</p><p>Int. J. Mol. Sci. 2021, 22, 5795. https://doi.org/10.3390/ijms22115795 https://www.mdpi.com/journal/ijms</p><p>Int. J. Mol. Sci. 2021, 22, 5795 9 of 34</p><p>Figure 1. Mechanism of action of representative exercise-induced myokines in the brain with ND. While there is experimental</p><p>evidence that some myokines penetrate the BBB (solid arrows from blood vessels through the BBB to the brain), others do</p><p>not so far (dashed arrows from the blood vessels through the BBB to the brain).</p><p>Gut microbiota and regulation of myokine-adipokine</p><p>function</p><p>Francesco Suriano1, Matthias Van Hul1 and Patrice D Cani</p><p>Both skeletal muscle and adipose tissue are considered as</p><p>endocrine organs due to their ability to produce and secrete</p><p>several bioactive peptides (e.g. myokines and adipokines).</p><p>Those bioactive molecules are well known for their capacity to</p><p>influence whole-body homeostasis and alterations in their</p><p>production/secretion are contributing to the development of</p><p>various metabolic disorders. While it is well accepted that</p><p>changes in the composition and functionality of the gut</p><p>microbiota are associated with the onset of several</p><p>pathological disorders (e.g. obesity, diabetes, and cancer), its</p><p>contribution to the regulation of the myokine-adipokine profile</p><p>and function remains largely unknown. This review will focus on</p><p>myokines and adipokines with a</p><p>special interest on their</p><p>interaction with the gut microbiota.</p><p>Address</p><p>UCLouvain, Université catholique de Louvain, WELBIO - Walloon</p><p>Excellence in Life Sciences and BIOtechnology, Louvain Drug Research</p><p>Institute, Metabolism and Nutrition Research Group, Brussels, Belgium</p><p>Corresponding author: Cani, Patrice D (patrice.cani@uclouvain.be)</p><p>@MicrObesity (P.D. Cani)</p><p>1 Equally contributors.</p><p>Current Opinion in Pharmacology 2020, 52:9–17</p><p>This review comes from a themed issue on Musculoskeletal</p><p>Edited by David M Mutch and David J Dyck</p><p>For a complete overview see the Issue and the Editorial</p><p>Available online 7th May 2020</p><p>https://doi.org/10.1016/j.coph.2020.03.006</p><p>1471-4892/ã 2020 The Authors. Published by Elsevier Ltd. This is an</p><p>open access article under the CC BY-NC-ND license (http://creative-</p><p>commons.org/licenses/by-nc-nd/4.0/).</p><p>Introduction</p><p>It is now well established that the gut microbiota can</p><p>influence an individual’s health status. Various underlying</p><p>mechanisms have been proposed and both direct and</p><p>indirect mechanisms of action have been described for</p><p>specific bacterial metabolites, such as short-chain fatty</p><p>acids (SCFAs), bile acids, branched chain amino acids,</p><p>indole propionic acid, and endocannabinoids [1]. In</p><p>additiontobacterial components,many endogenous factors</p><p>can be influenced by the gut microbiota. Myokines and</p><p>adipokines, produced and secreted by the skeletal muscles</p><p>and adipose tissues respectively, may be considered as</p><p>potential mediators. In this review, we start by introducing</p><p>myokines and adipokines and then focus on the crosstalk</p><p>between these molecules and the gut microbiota, taking a</p><p>particular interest on how they affect metabolic homeosta-</p><p>sis of the whole body.</p><p>Myokines</p><p>In the body, there are different type of muscles (skeletal,</p><p>cardiac, smooth),whichperformdifferent functionsbasedon</p><p>their location. They are mainly responsible for maintaining</p><p>and changing body posture, producing force and motion,</p><p>generating heat (both through shivering and non-shivering),</p><p>as well as facilitating movement of internal organs, such as</p><p>the heart, digestive organs, and blood vessels [2,3]. Skeletal</p><p>muscle is the largestorgan in the human body, accounting for</p><p>about 30% of body mass in women and 40% in men, though</p><p>muscle mass is affected by several conditions such as fasting,</p><p>physical inactivity, cancer, obesity, untreated diabetes, hor-</p><p>monal changes, heart failure, AIDS, chronic obstructive</p><p>pulmonary disease (COPD), or aging [4]. Skeletal muscle</p><p>acts as an endocrine organ, as muscle cells, called myocytes,</p><p>are able to synthesize and release several cytokines and</p><p>bioactive molecules in response to muscular contraction</p><p>(major physiological stimulus) and other stimuli (e.g. nutri-</p><p>ents, stress, environmental factors, metabolic dysfunction)</p><p>[2,5]. Interleukin (IL)-6 was the first muscle-secreted pro-</p><p>tein to be identified in the bloodstream [6]. In contrast to the</p><p>deleterious effects (e.g. insulin resistance, impaired glucose</p><p>metabolism) associated with elevated plasma concentration</p><p>of IL-6 during obesity and diabetes [7], the release of IL-6</p><p>after muscle contraction was associated locally (within the</p><p>muscle) with an increase in glucose uptake and fat oxidation</p><p>via an activation of AMP-activated protein kinase (AMPK)</p><p>and/or phosphatidylinositol 3-kinase (PI3-K) [6].These</p><p>effects are mediated by the binding of IL-6 to its specific</p><p>transmembrane alpha receptor (ILRa) which form a com-</p><p>plex that induces the homodimerization of the glycoprotein</p><p>(gp)-130 (also known as IL6Rb) leading to downstream</p><p>signaling pathways [6]. IL-6 may also act distally. In the</p><p>liver, it stimulates hepatic glucose production during</p><p>exercise. In the adipose tissue, it acts as a lipolytic hormone,</p><p>accelerating free-fatty acids release [6,8]. These beneficial</p><p>effects of IL-6 highlight the cross talk between skeletal</p><p>muscle and liver/adipose tissue. IL-6 secreted in response to</p><p>exercise was also associated to enhance insulin secretion by</p><p>increasingglucagon-likepeptide(GLP)-1secretionfromthe</p><p>intestinal L-cells and the pancreatic alpha-cells [9].</p><p>However, the different discrepancies observed for the role</p><p>of IL-6 on metabolism are still debated. It was also proposed</p><p>that IL-6 may arbitrate the anti-inflammatory effects of</p><p>exercise via the inhibition of pro-inflammatory cytokines,</p><p>like the endotoxin-induced tumor-necrosis factor</p><p>alpha (TNF-a), and the stimulation of anti-inflammatory</p><p>Available online at www.sciencedirect.com</p><p>ScienceDirect</p><p>www.sciencedirect.com Current Opinion in Pharmacology 2020, 52:9–17</p><p>considered an important tool to prevent or treat dysbiosis</p><p>associated-metabolic disorders [1].</p><p>Several endogenous and exogenous factors affect the</p><p>gut microbiota composition (e.g. diet, physical activity,</p><p>antibiotics, genetic background) [1] (Figure 1). Among</p><p>the different strategies that have been proposed to benefi-</p><p>cially modulate the gut microbiota, dietary interventions,</p><p>including supplementation with prebiotics (a substrate that</p><p>is selectively utilized by host microorganisms conferring a</p><p>health benefit, i.e. certain fibers and polyphenols) [50] and/</p><p>or probiotics (live microorganism that, when administered</p><p>in adequate amounts, improve host health) are considered</p><p>the most feasible and efficient [49].</p><p>There are several mechanisms by which the microbiota can</p><p>regulate host metabolism and health, many of which can be</p><p>traced back to microbial metabolites [1]. Among these</p><p>bacterial metabolites are the SCFAs that are produced</p><p>by bacterial fermentation of indigestible foods (i.e. dietary</p><p>source of polyphenols and complex carbohydrates) in</p><p>the gastrointestinal tract (Figure 1) [51,52]. SCFAs bind</p><p>to specific G protein coupled receptors (GPCRs) (i.e.</p><p>GPR41 and GPR43), and the resulting activation of those</p><p>receptors triggers the release of glucagon-like peptides</p><p>(GLP-1 and GLP-2) and peptide YY (PYY) (Figure 1)</p><p>which are involved in the control of energy homeostasis,</p><p>fat storage, improvement of the gut barrier function,</p><p>metabolic inflammation, glucose metabolism, and gut</p><p>transit time [51]. Metabolites coming from polyphenols</p><p>are able to activate AMPK via phosphorylation and</p><p>modulating some proteins involved in adipogenesis,</p><p>lipogenesis, and lipolysis in different tissues [52] (Figure 1).</p><p>Bile acids are also strongly influenced by the microbiota.</p><p>Indeed, primary bile acids are converted in secondary bile</p><p>12 Musculoskeletal</p><p>Figure 1</p><p>Extended</p><p>physical activity</p><p>Aging High-fat</p><p>diet</p><p>Dietary sources of polyphenols</p><p>and non-digestible</p><p>carbohydrates</p><p>Normal</p><p>physical activity</p><p>Probiotics</p><p>Mucus layers</p><p>Genetic</p><p>background</p><p>Antibiotics</p><p>Gut</p><p>microbes</p><p>Gut barrier function Gut barrier function</p><p>Inflammation</p><p>Pro-inflammatory myokines-adipokines</p><p>Anti-inflammatory myokines-adipokines</p><p>Fat oxidation Fat oxidation</p><p>Glucose utilization</p><p>AMPK</p><p>Blood vessel</p><p>Tight junction proteins</p><p>Receptors</p><p>Fat mass</p><p>Inflammation</p><p>PAMPs translocation Enterocytes L-cells</p><p>(GLP-1, PYY) Goblet cells Paneth cells</p><p>Altered myokine-adipokine profile Normal myokine-adipokine profile</p><p>Current Opinion in Pharmacology</p><p>Link between gut microbiota and myokine-adipokine function. Schematic illustration of the several factors influencing the gut microbiota</p><p>composition and how the gut microbiota and its derived metabolites have an important role in the control of the gut barrier function, bacterial</p><p>compounds translocation, metabolic functions, and myokine-adipokine production. Although the link between gut microbiota and myokine-</p><p>adipokine function is still unclear. AMPK, AMP-activated protein kinase; GLP-1, glucagon-like peptide-1; PYY, peptide YY; PAMPs, pathogen</p><p>associated molecular patterns; SCFAs, short-chain fatty acids.</p><p>Current Opinion in Pharmacology 2020, 52:9–17 www.sciencedirect.com</p><p>nutrients</p><p>Review</p><p>The Role of Exercise in the Interplay between</p><p>Myokines, Hepatokines, Osteokines, Adipokines,</p><p>and Modulation of Inflammation for Energy Substrate</p><p>Redistribution and Fat Mass Loss: A Review</p><p>Adrian M. Gonzalez-Gil 1,2 and Leticia Elizondo-Montemayor 1,2,3,*</p>