Myokines – muscle tissue hormones

Czech version

Authors: Zuzana Stránská; Štěpán Svačina
Authors‘ workplace: III. interní klinika 1. LF UK a VFN Praha, přednosta prof. MUDr. Štěpán Svačina, DrSc., MBA
Published in: Vnitř Lék 2015; 61(4): 365-368
Category: Reviews

Overview

Physical inactivity is demonstrably related to the manifestation of chronic diseases which significantly modify the quality and prognosis of life in a negative way. The benefits of exercise are surely mediated by many pathophysiological mechanisms interrelated in varying degrees, which have not yet been fully examined in their complexity. In the late 20th century it was positively proven that a working striated muscle really regulates the metabolic and physiological response in the other organs. These involve several hundred substances with autocrine, paracrine and endocrine effects. These proteins and peptides, if released into the blood stream, substantially affect the metabolism of distant organs. They were classified as “myokines“ (cytokines produced by myocytes). The identified myokines include e.g. IL4, IL6, IL7, IL15, myostatin, LIF (leukemia inhibitory factor), BDNF (brain-derived neurotrophic factor), IGF1 (insulin-like growth factor), FGF2 (fibroblast growth factor 2), FGF21, FSTL1 (follistatin-related protein 1), irisin, EPO (erythropoetin) and BAIBA (β-aminoisobutyric acid). Myokines have first of all an immunoregulatory role in the human body. Another important effect of myokines is, coincidentally also in the interaction with adipose tissue, the regulation of energy homeostasis. They also affect the growth of muscle fibres and their regeneration, stimulate angiogenesis, they are involved in the regulation of glucose metabolism and have a proven effect on lipids. Considering their diverse function, myokines present a prospective therapeutic goal in the treatment of disorders of muscle growth and regeneration as well as obesity. Another recent research moves toward uncovering of the “myokine resistance” as a result of long-term muscle inactivity and its association with chronic subclinical inflammation.

Key words:
physical exercise – inactivity – mortality – myokines – subclinical inflammation

Sources

1. Ekelund U, Ward HA, Norat T et al. Physical activity and all-cause mortality across levels of overall and abdominal adiposity in European men and women: the European Prospective Investigation into Cancer and Nutrition Study (EPIC). Am J Clin Nutr 2015; 101(3): 613–621. Dostupné z DOI: <http://dx.doi.org/10.3945/ajcn.114.100065>.

2. Pedersen BK. Body mass index-independent effect of fitness and physical activity for all-cause mortality. Scand J Med Sci Sports 2007; 17(3): 196–204.

3. Pedersen BK. Muscles and their myokines. J Exp Biol. 2011; 214(Pt 2): 337–346.

4. Pedersen BK. The diseasome of physical inactivity – and the role of myokines in muscle – fat cross talk. J Physiol 2009; 587(Pt 23): 5559–5568.

5. Tuomilehto J, Lindstrom J, Eriksson JG et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344(18): 1343–1350.

6. Nocon M, Hiemann T, Muller-Riemenschneider F et al. Association of physical activity with all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil 2008; 15(3): 239–246.

7. Wolin KY, Yan Y, Colditz GA et al. Physical activity and colon cancer prevention: a meta-analysis. Br J Cancer 2009; 100(4): 611–616.

8. Monninkhof EM, Elias SG, Vlems FA et al. Physical activity and breast cancer: a systematic review. Epidemiology 2007; 18(1): 137–157.

9. Paffenbarger RS Jr, Lee IM, Leung R. Physical activity and personal characteristics associated with depression and suicide in American college men. Acta Psychiatr Scand Suppl 1994; 377: 16–22.

10. Rovio S, Kareholt I, Helkala EL et al. Leisure-time physical activity at midlife and the risk of dementia and Alzheimer’s disease. Lancet Neurol 2005; 4(11): 705–711.

11. Goldstein MS. Humoral nature of the hypoglycemic factor of muscular work. Diabetes 1961; 10: 232–234.

12. Pedersen BK, Steensberg A, Fischer C et al. Searching for the exercise factor: is IL-6 a candidate? J Muscle Res Cell Motil 2003; 24(2–3): 113–119.

13. Asmussen E. Ventilation at transition from rest to exercise. Acta Physiol Scand 1973; 89(1): 68–78.

14. Mohr T, Andersen JL, Biering-Sorensen F et al. Long-term adaptation to electrically induced cycle training in severe spinal cord injured individuals. Spinal Cord 1997; 35(1): 1–16. Erratum in Spinal Cord 1997; 35(4): 262.

15. Iizuka K, Machida T, Hirafuji M. Skeletal muscle is an endocrine organ. J Pharmacol Sci 2014; 125(2): 125–131.

16. Pedersen BK. Muscle as a secretory organ. Compr Physiol 2013; 3(3): 1337–1362.

17. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 1997; 387(6628): 83–90.

18. Barra NG, Reid S, MacKenzie R et al. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity (Silver Spring) 2010; 18(8): 1601–1607.

19. Spangenburg EE, Booth FW. Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(-/-) mouse. Cytokine 2006; 34(3–4): 125–130.

20. Kurek J, Bower J, Romanella M et al. Leukaemia inhibitory factor treatment stimulates muscle regeneration in the mdx mouse. Neurosci Lett 1996; 212(3): 167–170.

21. Sakuma K, Watanabe K, Sano M et al. Postnatal profiles of myogenic regulatory factors and the receptors of TGF-beta 2, LIF and IGF-I in the gastrocnemius and rectus femoris muscles of dy mouse. Acta neuropathol 2000; 99(2): 169–176.

22. Hamrick MW, McNeil PL, Patterson SL. Role of muscle-derived growth factors in bone formation. J Musculoskelet Neuronal Interact 2010; 10(1): 64–70.

23. Liang H, Pun S, Wronski TJ. Bone anabolic effects of basic fibroblast growth factor in ovariectomized rats. Endocrinology 1999; 140(12): 5780–5788.

24. Wu Y, Yakar S, Zhao L et al. Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 2002; 62(4): 1030–1035.

25. Nonogaki K, Fuller GM, Fuentes NL et al. Interleukin-6 stimulates hepatic triglyceride secretion in rats. Endocrinology 1995; 136(5): 2143–2149.

26. van Hall G, Steensberg A, Sacchetti M et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin Endocrinol Metab 2003; 88(7): 3005–3010.

27. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 2008; 88(4): 1379–1406.

28. Fischer CP. Interleukin-6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev 2006; 12: 6–33.

29. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem 2003; 278(46): 45777–45784.

30. Kim HJ, Higashimori T, Park SY et al. Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo. Diabetes 2004; 53(4): 1060–1067.

31. Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 2004; 24(12): 5434–5446.

32. Carey AL, Steinberg GR, Macaulay SL et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 2006; 55(10): 2688–2697.

33. Febbraio MA, Hiscock N, Sacchetti M et al. Interleukin-6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004; 53(7): 1643–1648.

34. Wallenius V, Wallenius K, Ahren B et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 2002; 8(1): 75–79.

35. Ellingsgaard H, Ehses JA, Hammar EB et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc Natl Acad Sci USA 2008; 105(35): 13163–13168.

36. Ellingsgaard H, Hauselmann I, Schuler Bet al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells.. Nat Med 2011; 17(11): 1481–1489.

37. Svacina S. Incretin therapy and the metabolic syndrome. Vnitř Lék 2011; 57(4): 417–421.

38. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR et al. Influence of mode and carbohydrate on the cytokine response to heavy exertion. Med Sci Sports Exerc 1998; 30(5): 671–678.

39. Starkie RL, Rolland J, Angus DJ et al. Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-alpha levels after prolonged running. Am J Physiol Cell Physiol 2001; 280(4): C769-C774.

40. Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 2005; 33(3): 114–119.

41. Lavoie ME, Rabasa-Lhoret R, Doucet E et al. Association between physical activity energy expenditure and inflammatory markers in sedentary overweight and obese women. Int J Obes (Lond) 2010; 34(9): 1387–1395.

42. Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on chronic inflammation. Clin Chim Acta 2010; 411(11–12): 785–793.

43. Pedersen BK. A muscular twist on the fate of fat. N Engl J Med 2012; 366(16): 1544–1545.

44. Ginter E, Simko V. Recent data on obesity research: beta-aminoisobutyric acid. Bratisl Lek Listy 2014; 115(8): 492–493.

45. Bostrom P, Wu J, Jedrychowski MP et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012; 481(7382): 463–468.

46. Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a metabolic regulator that plays a role in the adaptation to ketosis. Am J Clin Nutr 2011; 93(4): 901S-905S.

47. Hojman P, Brolin C, Gissel H et al. Erythropoietin over-expression protects against diet-induced obesity in mice through increased fat oxidation in muscles. PloS one 2009; 4(6): e5894. Dostupné z DOI: <http://doi: 10.1371/journal.pone.0005894>.