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
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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
Diseasome of physical inactivity3
Pedersen, 2011
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
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Pedersen, 2011
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
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Pedersen, 2011
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
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Pedersen, 2011
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
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Pedersen, 2011
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
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Anti-inflammatory cytokines released after exercise
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Pedersen, 2009
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Munoz-Canoves, 2013
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
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Pedersen, 2011
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
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Pedersen, 2011
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
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Pedersen, 2011
brain-derived neurotrophic factor
BDNF regulate fat metabolism, with a subsequent effect on the size of adipose tissue In autocrine or paracrine fashion
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Pedersen, 2011
Diseasome of low BDNF similar to that of physical inactivity
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Pedersen, 2009
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
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Itoh, 2014
FGF21 functions17
Itoh, 2014
FGF21 as biomarker of diseases18
Itoh, 2014
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
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Itoh, 2014
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
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Irving, 2014
Putative effect of irisin on browning of white adipose tissue
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Irving, 2014
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
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Irving, 2014
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
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Irving, 2014
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
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Irving, 2014
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.
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Broholm, 2013
IL-6 family and their receptor
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Broholm, 2013
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
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Broholm, 2013
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
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Broholm, 2013
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
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Broholm, 2013
muscle-derived LIF in muscle hypertrophy and regeneration
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Broholm, 2013
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
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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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