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The Impact of Myokines: Understanding Muscle-Derived Peptides for Health

Explore the role of myokines in paracrine and endocrine effects, the consequences of physical inactivity on muscle function, and the interaction between myokines and fat metabolism. Learn about interleukin-6 and other key myokines in regulating inflammation and exercise-induced effects on cytokines.

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The Impact of Myokines: Understanding Muscle-Derived Peptides for Health

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  1. Myokines • cytokines and other peptides that are produced, expressed, and released by muscle fibers • exert paracrine or endocrine effects • explain multiple consequences of a physically inactive life style • If the endocrine function of the muscle is NOT stimulated through contractions, this will cause malfunction of several organs and tissues

  2. Myokines • interleukin IL-6, IL-8, IL-15, BDNF, LIF, FGF21, Follistatin-like-1 • contracting skeletal muscles release myokines with functions: • hormone-like function, specific endocrine effects on visceral fat and other ectopic fat deposits. • work locally within the muscle via paracrine mechanisms, on signaling pathways involved in fat oxidation. • Mediating inflammatory pathway • organ cross talk, including muscle–fat cross talk

  3. Diseasome of physical inactivity Pedersen, 2011

  4. Myokines and visceral fat • Hypothesis: physical inactivity is an independent cause of fat accumulation in ‘the wrong places’. • Exercise ↓ chronic diseases associated with chronic inflammation • One reason: ↓ visceral fat Pedersen, 2011

  5. Interleukin-6 • First identified, most studied myokine • ↑100 X in blood during exercise • IL-6 is markedly produced and released in the post exercise period when insulin action is enhanced • but, IL-6 has also been associated with obesity and reduced insulin action Pedersen, 2011

  6. IL-6 • Within skeletal muscle, IL-6 acts locally to activate AMP-kinase and/or PI3-kinase • ↑ glucose uptake and fat oxidation in muscle • Hormone-like:↑hepatic glucose production, ↑lipolysis in adipose tissue • muscular IL-6 NOT activate NF-kB signaling • exercise-induced IL-6 response is NOT mediating strong pro-inflammatory activities • IL-6 in macrophage, activate NF-kB, ↑inflammation Pedersen, 2011

  7. IL-6 • Following exercise, IL-6 induce high circulating levels of IL-6 are followed by ↑ IL-1ra and IL-10, anti-inflammatory cytokines • IL-1ra inhibit IL-1 function, bind to IL-1 receptor but induce no response • Muscle-derived IL-6 ↓TNF-alpha, ↓IL-1 production • Part of the mechanism for exercise-induced anti-inflammatory effect Pedersen, 2011

  8. Anti-inflammatory effect of exercise • Exercise increases the release of epinephrine, cortisol, growth hormone, prolactin • immunomodulatory effects • 3 hr cycling, or infusion of IL-6, ↓ TNF-a secretion induced by endotoxin • Typically, IL-6 is the first cytokine released into the circulation during exercise • Then IL-1ra, IL-10, also anti-inflammatory • pro-inflammatory cytokines,TNF-a and IL-1b, in general NOT increase with exercise

  9. Anti-inflammatory cytokines released after exercise Pedersen, 2009

  10. Munoz-Canoves, 2013

  11. IL-15: muscle-fat cross talk • IL-15 accumulate within the muscle after regular training. • Negative association between plasma IL-15 concentration and trunk fat mass, but not limb fat mass, in humans • IL-15 overexpressed in mouse muscles, ↓ visceral fat mass, but not subcutaneous fat mass Pedersen, 2011

  12. brain-derived neurotrophic factor • BDNF regulate survival, growth, and maintenance of neurons, learning and memory • Alzheimer’s patients: ↓ BDNF expression in Hippocampal, ↓ BDNF in plasma • impaired memory and general cognitive function in ageing women associated with ↓ plasma BDNF • ↓ BDNF in plasma associated with ↑ mortality in old women, ↑ obesity, ↑ type 2 DM, ↑ depression, ↑ insulin resistance Pedersen, 2011

  13. brain-derived neurotrophic factor • In humans, cerebral output of BDNF at basal condition, • ↓ cerebral output of during hyperglycaemic clamp • ↑ BDNF mRNA and protein in human skeletal muscle after exercise • muscle-derived BDNF not to be released into the circulation • BDNF ↑ phosphorylation of AMPK and ACC  ↑ fat oxidation • ACC (acetyl-CoA carboxylase): acetyl-CoA  malonyl-CoA Pedersen, 2011

  14. brain-derived neurotrophic factor • BDNF regulate fat metabolism, with a subsequent effect on the size of adipose tissue • In autocrine or paracrine fashion Pedersen, 2011

  15. Diseasome of low BDNF similar to that of physical inactivity Pedersen, 2009

  16. Fibroblast growth factor 21 • FGF21 is a unique FGF with metabolic, but not proliferative activities • Fibroblast growth factor (FGF) family: signaling proteins with diverse functions in development and metabolism • FGF 21 as hepatokine, adipokine, and myokine in metabolism, injury protection, and diseases Itoh, 2014

  17. FGF21 functions Itoh, 2014

  18. FGF21 as biomarker of diseases Itoh, 2014

  19. FGF21 • expression of FGF21 regulated by PI3K/Akt1 signaling pathway • Down-stream of insulin signal • In Akt1 transgenic mice: ↑ Skeletal muscle hypertrophy, ↑ FGF21 • ↑ FGF21 in muscle by various types of stress • Mitochondria dysfunction, respiratory chain inhibitors • ↑ protection against diet-induced obesity and insulin resistance • increased browning of white adipose tissue (↑ uncoupling protein 1, UCP-1) in an endocrine manner Itoh, 2014

  20. irisin • Irisin: exercise-induced myokine, with potential to induce “browning” of white adipocytes in mice • BAT higher metabolic rate than WAT, mostly due to expression of UCP1 • In mouse, ↑ PGC1-α in muscle ↑ browning of subcutaneous WAT • similar to traditional exercise effects Irving, 2014

  21. Putative effect of irisin on browning of white adipose tissue Irving, 2014

  22. irisin • cultured primary mouse subcutaneous adipocytes with conditioned media from PGC1-α over expressing mouse myocytes • ↑ expression of brown-fat-specific genes • One or more myokine responsible for the change • Target gene: Fibronectin type III domain-containing 5 (FNDC5), protein product named ‘irisin’ • secreted form of irisin was highly homologous between mouse and humans • N-terminal (extracellular) fragments of irisin in cell culture media and/or plasma Irving, 2014

  23. Irisin in humans • Exercise training ↑ irisin in plasma and muscle expression? Inconclusive • No effect in a randomized clinical trial of (n=102) middle aged participants after 26 wk training • Muscle Irisin NO effect on browning of human pre-adipocytes Irving, 2014

  24. Irisin • Expression of irisin in WAT < 5% of that observed in skeletal muscle in humans • Although may serve as adipokine to regulate • ↓ Irisin gene expression in muscle and adipose tissue, ↓irisin in blood, in type 2 DM and obese humans • Irisin gene expression in visceral and subcutaneous WAT positively associated with brown adipose tissue markers (PRDM16 and UCP1) in humans Irving, 2014

  25. Leukaemia inhibitory factor • Originally found secreted from ascites tumour cells, with ability to induce terminal differentiation of myeloid leukaemic cells • LIF, synthesis and released following exercise, stimulates muscle satellite cell proliferation and is involved in muscle hypertrophy and regeneration • LIF may be produced by skeletal muscle during exercise to contribute to local aspects of muscle adaptation to exercise. Broholm, 2013

  26. IL-6 family and their receptor Broholm, 2013

  27. Leukaemia inhibitory factor • exercise induces LIF mRNA in human skeletal muscle • ↑ 4X after endurance, 9X after heavy resistance • ↓gradually throughout the post-exercise period • LIF protein levels remain unaltered, repetitive bouts of exercise are necessary Broholm, 2013

  28. LIF and muscle hypertrophy • LIF ↑ proliferation of myoblast and satellite cells, while preventing premature differentiation, by ↑ signaling cascade involving JAK1, STAT1 and STAT3 • muscle adaptation and hypertrophy depend on the addition of new myonuclei by way of proliferation and further fusion of satellite cells to the adult muscle fibers • LIF plays a role Broholm, 2013

  29. LIF and muscle regeneration • LIF ↑ muscle regeneration in mice suffering from muscle dystrophy • LIF restores the hypertrophic response to increased loading in LIF (-/-) mice • LIF an important factor in skeletal muscle hypertrophy Broholm, 2013

  30. muscle-derived LIF in muscle hypertrophy and regeneration Broholm, 2013

  31. Conclusions • identification of skeletal muscle as an endocrine organ that produces and releases myokines expands our knowledge on how muscle-derived factors contribute to exercise adaptation, inflammation, and various chronic diseases • Myokines appear to have important local effects within the muscle, including effects on metabolism, angiogenesis and muscle growth • Myokines also have endocrinological functions

  32. Conclusions • IL-6 influences metabolism in skeletal muscle, adipose tissue and the liver, regulating satellite cell-mediated hypertrophy • IL-8 affect angiogenesis • IL-15 ↓adipose tissue mass • LIF regulate satellite cells, similar to IL-6. • IL-6 and LIF share the gp130 receptor component of their signalling complexes and show high homology in their tertiary structures • timing and balance between these cytokines still unclear

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