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Myokines

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

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Myokines

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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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