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Myokines
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cytokines and other peptides that are
produced, expressed, and released by muscle
fibers
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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
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interleukin IL-6, IL-8, IL-15, BDNF, LIF, FGF21,
Follistatin-like-1
contracting skeletal muscles release myokines with
functions:
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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 inactivity
Pedersen, 2011
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Myokines and visceral fat
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Hypothesis: physical inactivity is an
independent cause of fat accumulation in ‘the
wrong places’.
Exercise ↓ chronic diseases associated with
chronic inflammation
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One reason: ↓ visceral fat
Pedersen, 2011
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Interleukin-6
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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
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IL-6
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Within skeletal muscle, IL-6 acts locally to activate
AMP-kinase and/or PI3-kinase
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↑ glucose uptake and fat oxidation in muscle
Hormone-like:↑hepatic glucose production, ↑lipolysis in
adipose tissue
muscular IL-6 NOT activate NF-kB signaling
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exercise-induced IL-6 response is NOT mediating strong
pro-inflammatory activities
IL-6 in macrophage, activate NF-kB, ↑inflammation
Pedersen, 2011
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IL-6
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Following exercise, IL-6 induce high
circulating levels of IL-6 are followed by ↑
IL-1ra and IL-10, anti-inflammatory
cytokines
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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
Pedersen, 2011
anti-inflammatory effect
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Anti-inflammatory effect of exercise
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Exercise increases the release of epinephrine,
cortisol, growth hormone, prolactin
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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
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immunomodulatory effects
Then IL-1ra, IL-10, also anti-inflammatory
pro-inflammatory cytokines,TNF-a and IL1b, in general NOT increase with exercise
Anti-inflammatory cytokines
released after exercise
Pedersen, 2009
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MunozCanoves, 2013
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IL-15: muscle-fat cross talk
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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
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brain-derived neurotrophic factor
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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
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brain-derived neurotrophic factor
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In humans, cerebral output of BDNF at basal
condition,
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↑ BDNF mRNA and protein in human skeletal
muscle after exercise
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↓ cerebral output of during hyperglycaemic clamp
muscle-derived BDNF not to be released into the
circulation
BDNF ↑ phosphorylation of AMPK and ACC  ↑
fat oxidation
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ACC (acetyl-CoA carboxylase): acetyl-CoA  malonylCoA
Pedersen, 2011
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brain-derived neurotrophic factor
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BDNF regulate fat metabolism, with a
subsequent effect on the size of adipose
tissue
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In autocrine or paracrine fashion
Pedersen, 2011
Diseasome of low BDNF similar
to that of physical inactivity
Pedersen, 2009
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Fibroblast growth factor 21
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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
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FGF21 functions
Itoh, 2014
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FGF21 as biomarker of diseases
Itoh, 2014
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FGF21
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expression of FGF21 regulated by PI3K/Akt1
signaling pathway
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Down-stream of insulin signal
In Akt1 transgenic mice: ↑ Skeletal muscle hypertrophy,
↑ FGF21
↑ FGF21 in muscle by various types of stress
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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
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irisin
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Irisin: exercise-induced myokine, with
potential to induce “browning” of white
adipocytes in mice
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BAT higher metabolic rate than WAT, mostly
due to expression of UCP1
In mouse, ↑ PGC1-α in muscle ↑ browning of
subcutaneous WAT
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similar to traditional exercise effects
Irving, 2014
Putative effect of irisin on browning of
white adipose tissue
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Irving, 2014
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irisin
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cultured primary mouse subcutaneous adipocytes
with conditioned media from PGC1-α over
expressing mouse myocytes
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↑ 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
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Irisin in humans
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Exercise training ↑ irisin in plasma and
muscle expression? Inconclusive
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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
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Irisin
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Expression of irisin in WAT < 5% of that
observed in skeletal muscle in humans
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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
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Leukaemia inhibitory factor
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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
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IL-6 family and their receptor
Broholm, 2013
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Leukaemia inhibitory factor
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exercise induces LIF mRNA in human
skeletal muscle
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↑ 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
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LIF and muscle hypertrophy
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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
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LIF plays a role
Broholm, 2013
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LIF and muscle regeneration
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LIF ↑ muscle regeneration in mice suffering
from muscle dystrophy
LIF restores the hypertrophic response to
increased loading in LIF (-/-) mice
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LIF an important factor in skeletal muscle
hypertrophy
Broholm, 2013
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muscle-derived LIF in muscle
hypertrophy and regeneration
Broholm, 2013
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Conclusions
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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
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IL-6 influences metabolism in skeletal muscle,
adipose tissue and the liver, regulating satellite cellmediated hypertrophy
IL-8 affect angiogenesis
IL-15 ↓adipose tissue mass
LIF regulate satellite cells, similar to IL-6.
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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