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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