- Visibility 303 Views
- Downloads 337 Downloads
- Permissions
- DOI 10.18231/j.ijcap.v.12.i.3.4
-
CrossMark
- Citation
Exercise-induced myokines: Molecular mechanisms and systemic health benefits
The skeletal muscle functions as an endocrine organ that secretes bioactive molecules called myokines during exercise. These exercise-induced myokines, including irisin, interleukin-6 (IL-6), and brain-derived neurotrophic factor (BDNF), mediate crosstalk between muscles and distant organs, regulating systemic metabolism, neuroprotection, and inflammation. Irisin, cleaved from FNDC5, induces browning of white adipose tissue and crosses the blood-brain barrier to increase brain-derived neurotrophic factor (BDNF) and synaptic plasticity. Muscle-derived IL-6 exhibits dual roles, stimulating glucose uptake and lipolysis while exerting anti-inflammatory effects by inhibiting TNF-α and inducing IL-1ra and IL-10 production. BDNF, primarily originating from contracting muscle, enhances hippocampal neurogenesis and cognitive function. Myokine secretion exhibits intensity-dependent patterns, with high-intensity interval training (HIIT) preferentially upregulating PGC-1α-dependent myokines, such as irisin. However, knowledge gaps remain regarding myokine receptor systems, temporal dynamics, dose-response relationships, and interindividual variabilities. Methodological challenges include standardization of sampling protocols, utilization of advanced detection methods, and improvement of experimental design and data reporting. Myokines represent a fundamental mechanism underlying the systemic health benefits of exercise and offer therapeutic potential in metabolic and neurodegenerative diseases. Understanding myokine signaling provides critical insights for developing exercise-mimetic therapies and personalized medicine approaches. Future research should on developing myokine biomarkers, optimizing exercise regimens, and exploring pharmacological modulation to harness the endocrine potential of skeletal muscle.
References
- Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev. 2008;88(4):1379-
- Steensberg A, van Hall G, Osada T, Sacchetti M, Saltin B, Klarlund Pedersen B.et al. Production of interleukin-6 in contracting human skeletal muscles can account for the exercise-induced increase in plasma interleukin-6. J Physiol. 2000;529(1):237-42.
- Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard P. et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil. 2003;24(2-3):113-9.
- Bostrom P, Jedrychowski MP, Korde A, Ye L, Lo JC. A PGC1-α- dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463-8.
- Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol. 2012;8(8):457-65.
- Rasmussen P, Brassard P, Adser H, et al. Evidence for a release of brain-derived neurotrophic factor from the brain during exercise. Exp Physiol. 2009;94(10):1062-9.
- McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF -β superfamily member. Nature. 1997;387(6628):83-90.
- Aoi W, Naito Y, Takagi T. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut. 2013;62(6):882-9.
- Rose AJ, Richter EA. Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology (Bethesda). 2005;20:260- 70
- Steensberg A, Febbraio MA, Osada T, Schjerling P, van Hall G, Saltin B, Pedersen BK. Interleukin-6 production in contracting human skeletal muscle is influenced by pre-exercise muscle glycogen content. J Physiol. 2001;537(Pt 2):633-9.
- Huh JY, Mougios V, Kabasakalis A, Fatouros I, Siopi A, Douroudos II, Filippaios A, Panagiotou G, Park KH, Mantzoros CS. Exercise- induced irisin secretion is independent of age or fitness level and increased irisin may directly modulate muscle metabolism through AMPK activation. J Clin Endocrinol Metab. 2014;99(11):E2154-
- Whitham M, Parker BL, Friedrichsen M. Extracellular vesicles provide a means for tissue crosstalk during exercise. Cell Metab. 2018;27(1):237-51
- Severinsen MCK, Pedersen BK. Muscle-Organ Crosstalk: The Emerging Roles of Myokines. Endocr Rev. 2020:41(4):594–609.
- Leal LG, Lopes MA, Batista ML Jr. Physical Exercise-Induced Myokines and Muscle-Adipose Tissue Crosstalk: A Review of Current Knowledge and the Implications for Health and Metabolic Diseases. Front Physiol. 2018;9:1307.
- Pedersen BK. Muscles and their myokines. J Exp Biol. 214(2):337-
- Schnyder S, Handschin C. Skeletal muscle as an endocrine organ: PGC-1α, myokines and exercise. Bone. 2015:115-25.
- Chow LS, Gerszten RE, Taylor JM, Pedersen BK, van Praag H, Trappe S. et al. Exerkines in health, resilience and disease. Nat Rev Endocrinol. 2022;18(5):273-89
- Delezie J, Handschin C. Endocrine Crosstalk Between Skeletal Muscle and the Brain. Front Neurol. 2018;9:698.
- Severinsen MCK, Pedersen BK. Muscle-Organ Crosstalk: The Emerging Roles of Myokines. Endocr Rev. 2020;41(4):594–609.
- Piccirillo R. Exercise-Induced Myokines With Therapeutic Potential for Muscle Wasting. Front Physiol. 2019;10:287.
- Whitham M, Febbraio MA. The ever-expanding myokinome: discovery challenges and therapeutic implications. Nat Rev Drug Discov. 2016;15(10):719-29.
- Tsuchiya Y, Ando D, Goto K, Kiuchi M, Yamakita M, Koyama K. High-intensity exercise causes greater irisin response compared with low-intensity exercise under similar energy consumption. Tohoku J Exp Med. 2014;233(2):135-40.
- Lira VA, Benton CR, Yan Z, Bonen A. PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity. Am J Physiol Endocrinol Metab. 2010;299(2):145-61.
- Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev. 2006;12:6-33.
- Hulmi JJ, Walker S, Ahtiainen JP, Nyman K, Kraemer WJ, Häkkinen K. Molecular signaling in muscle is affected by the specificity of resistance exercise protocol. Scand J Med Sci Sports. 2012;22(2):240-8.
- Peake JM, Neubauer O, Della Gatta PA, Nosaka K. Muscle damage and inflammation during recovery from exercise. J Appl Physiol. 2017;122(3):559-70.
- Schjerve IE, Tyldum GA, Tjønna AE, Stølen T, Loennechen JP, Hansen HE. et al. Both aerobic endurance and strength training 106 Kour and Sharma / Indian Journal of Clinical Anatomy and Physiology 2025;12(3):101–106 programmes improve cardiovascular health in obese adults. Clin Sci (Lond). 2008;115(9):283-93.
- Jedrychowski MP, Wrann CD, Paulo JA, Gerber KK, Szpyt J, Robinson MM, Nair KS, Gygi SP, Spiegelman BM. Detection and Quantitation of Circulating Human Irisin by Tandem Mass Spectrometry. Cell Metab. 2015;22(4):734-40.
- Perakakis N, Triantafyllou GA, Fernández-Real JM, Huh JY, Park KH, Seufert J, Mantzoros CS. Physiology and role of irisin in glucose homeostasis. Nat Rev Endocrinol. 2017;13(6):324-37.
- Buford TW, Roberts MD, Church TS. Toward exercise as personalized medicine. Sports Med. 2013;43(3):157-65.
- Munukka E, Ahtiainen JP, Puigbó P, Jalkanen S, Pahkala K, Keskitalo A. et al. Six-Week Endurance Exercise Alters Gut Metagenome That Is not Reflected in Systemic Metabolism in Over- weight Women. Front Microbiol. 2018;9:2323.
- Lindholm ME, Marabita F, Gomez-Cabrero D. An integrative analysis reveals coordinated reprogramming of the epigenome and the transcriptome in human skeletal muscle after training. Epigenetics. 2014;9(12):1557-69.
- Gyriki D, Nikolaidis CG, Bezirtzoglou E, Voidarou C, Stavropoulou E, Tsigalou C. The gut microbiota and aging: interactions, implications, and interventions. Front Aging. 2025;6:1452917
- Lindholm ME, Marabita F, Gomez-Cabrero D, Rundqvist H, Ekström TJ, Tegnér J, Sundberg CJ. et al. An integrative analysis reveals coordinated reprogramming of the epigenome and the transcriptome in human skeletal muscle after training. Epigenetics. 20149(12):1557-69.
- Freyssenet D, Di Carlo M, Hood DA. Calcium-dependent regulation of cytochrome c gene expression in skeletal muscle cells. Identification of a protein kinase c-dependent pathway. J Biol Chem. 1999;274(14):9305-11.
- Nybo L, Nielsen B, Pedersen BK, Moller K, Secher NH. Interleukin-6 release from the human brain during prolonged exercise. J Physiol. 2002;542(Pt 3):991-5.
- Barrès R, Yan J, Egan B, Treebak JT, Rasmussen M, Fritz T. et al. cute exercise remodels promoter methylation in human skeletal muscle. Cell Metab. 2012;15(3):405-11.
- Rose-John S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci. 2012;8(9):1237-47.
- Schett G, Dayer JM, Manger B. Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol. 2016;12(1):14-24.
- Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 2004;113(9):1271-6.
- Knudsen JG, Murholm M, Carey AL, Biensø RS, Basse AL, Allen TL. et al. Role of IL-6 in exercise training- and cold-induced UCP1 expression in subcutaneous white adipose tissue. PLoS One. 2014;9(1):e84910.
- Kelly M, Gauthier MS, Saha AK, Ruderman NB. Activation of AMP-activated protein kinase by interleukin-6 in rat skeletal muscle: association with changes in cAMP, energy state, and endogenous fuel mobilization. Diabetes. 2009;58(9):1953-60.
- Scheller J, Chalaris A, Schmidt-Arras D, Rose-John S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim Biophys Acta. 2011;1813(5):878-88.
- Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-59.
- Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, Lin JD, Greenberg ME, Spiegelman BM. Exercise induces hippocampal BDNF through a PGC-1α/FNDC5 pathway. Cell Metab. 2013;18(5):649-59.
- Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. FASEB J. 2003:17(8):884-6.
- Erickson KI, Voss MW, Prakash RS, Basak C, Szabo A, Chaddock L, Kim JS, Heo S, Alves H, White SM, Wojcicki TR, Mailey E, Vieira VJ, Martin SA, Pence BD, Woods JA, McAuley E, Kramer AF. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U.S.A. 2011;108(7):3017-22.
- Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab. 2014;19(2):302-9.
- Wedell-Neergaard AS, Lang Lehrskov L, Christensen RH, Legaard GE, Dorph E, Larsen MK, Launbo N. et al. Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial. Cell Metab. 2019;29(4):844-55.
- Polyzos SA, Anastasilakis AD, Efstathiadou ZA, Makras P, Perakakis N, Kountouras J, Mantzoros CS. Irisin in metabolic diseases. Endocrine. 2018 ;59(2):260-74.
- Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Invest. 2017 Aug;47(8):600-
- Lourenco MV, Frozza RL, de Freitas GB, Zhang H, Kincheski GC, Ribeiro FC. et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med. 2019;25(1):165-75.
How to Cite This Article
Vancouver
Kour H, Sharma HB. Exercise-induced myokines: Molecular mechanisms and systemic health benefits [Internet]. Indian J Clin Anat Physiol. 2025 [cited 2025 Oct 21];12(3):101-106. Available from: https://doi.org/10.18231/j.ijcap.v.12.i.3.4
APA
Kour, H., Sharma, H. B. (2025). Exercise-induced myokines: Molecular mechanisms and systemic health benefits. Indian J Clin Anat Physiol, 12(3), 101-106. https://doi.org/10.18231/j.ijcap.v.12.i.3.4
MLA
Kour, Harpreet, Sharma, Hanjabam Barun. "Exercise-induced myokines: Molecular mechanisms and systemic health benefits." Indian J Clin Anat Physiol, vol. 12, no. 3, 2025, pp. 101-106. https://doi.org/10.18231/j.ijcap.v.12.i.3.4
Chicago
Kour, H., Sharma, H. B.. "Exercise-induced myokines: Molecular mechanisms and systemic health benefits." Indian J Clin Anat Physiol 12, no. 3 (2025): 101-106. https://doi.org/10.18231/j.ijcap.v.12.i.3.4