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Muscle as a Secretory Organ

Bente K. Pedersen*1

ABSTRACT
Skeletal muscle is the largest organ in the body. Skeletal muscles are primarily characterized
by their mechanical activity required for posture, movement, and breathing, which depends on
muscle fiber contractions. However, skeletal muscle is not just a component in our locomotor
system. Recent evidence has identified skeletal muscle as a secretory organ. We have suggested
that cytokines and other peptides that are produced, expressed, and released by muscle fibers
and exert either autocrine, paracrine, or endocrine effects should be classified as “myokines.”
The muscle secretome consists of several hundred secreted peptides. This finding provides a
conceptual basis and a whole new paradigm for understanding how muscles communicate
with other organs such as adipose tissue, liver, pancreas, bones, and brain. In addition, several
myokines exert their effects within the muscle itself. Many proteins produced by skeletal muscle are
dependent upon contraction. Therefore, it is likely that myokines may contribute in the mediation
of the health benefits of exercise. 
C 2013 American Physiological Society. Compr Physiol 3:1337-

1362, 2013.

Introduction physical activity. Such factors might directly or indirectly in-

Skeletal muscle can be identified as an organ that produces and
releases cytokines and other peptides, which we have named
“myokines” (170). Given that skeletal muscle is the largest or-
gan in the human body, the discovery that contracting skeletal
muscle secretes proteins sets a novel paradigm: skeletal mus-
cle is a secretory organ producing and releasing myokines in
response to contraction, which can influence metabolism and
function of both muscle tissue and other tissues and organs,
Figure 1.
History—Myokines in the Context of
Exercise Physiology
For nearly half a century, researchers hypothesized that skele-
tal muscle cells possessed a “humoral” factor that was released
in response to increased glucose demand during contraction
(69). Due to lack of more precise knowledge, the unidentified
contraction-induced factor was named “the work stimulus,”
“the work factor,” or the “exercise factor” (178).
The early view on the exercise factor concept was pred-
icated on the fact that contracting skeletal muscle mediates
metabolic and physiologic responses in other organs, which
are not mediated via the nervous system.
This view has been supported by the fact that electrical
stimulation of paralyzed muscles in spinal cord injured pa-
tients with no afferent or efferent impulses induces many of
the same physiological changes as in intact human beings
(110, 136). Therefore, it was clear that contracting skeletal
muscles were able to communicate to other organs via hu-
moral factors, which are released into the circulation during
fluence the function of other organs such as the adipose tissue,
the liver, the cardiovascular system, and the brain.
In our view, the pluralis form “exercise factors” would be
more applicable given the fact that multiple metabolic and
physiologic changes are induced by exercise. This view has
been substantiated by the identification of skeletal muscle as
a secretory organ, which produces several secreted factors.
It has been obvious that several effects of exercise might be
explained by the release of one or more humoral factors from
the muscle that either directly or indirectly could influence
metabolism and function in other organs.
An example is the fact that the dramatically increased glu-
cose uptake by contracting skeletal muscle corresponds to an
increased glucose production by the liver, whereby glucose
homeostasis is maintained. It is not fully understood how con-
tracting muscles modulate metabolism in the liver, but it is ob-
vious that a muscle-derived humoral factor could be involved.
Another example is given when, in response to exercise, adi-
pose tissue increases the release of free fatty acids (FFAs) into
the circulation. Again, it is not known how contracting skeletal
muscle and adipose tissue communicate. Yet another example
is found in the notion that many individuals claim a stronger
feeling of pleasantness after exercise. This may be ascribed
* Correspondence to bkp@rh.dk
1 The Centre of Inflammation and Metabolism at Department of
Infectious Diseases, and Copenhagen Muscle Research Centre,
The Faculty of Health Sciences, University of Copenhagen,
Copenhagen, Denmark
Published online, July 2013 (comprehensivephysiology.com)
DOI: 10.1002/cphy.c120033
Copyright 
C American Physiological Society

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Muscle as a Secretory Organ Comprehensive Physiology

Browning
Lipolysis

Irisin Follistatin
LIF Hepatic glucose
IL-6 IL-4 production
IL-6
during exercise
IL-7
Unknown
IL-15 Myostatin Hepatic CXCL-1
IL-6 exercise
IL-6 production
stimulus
BDNF Hypertrophy
IL-6 Lipolysis IL-6
AMPK
Glucose
uptake
Fat oxidation
Angiogenesis

IGF-1 FGF-21 FSTL-1

FGF-2 IL-8?
IL-6 CXCL-1?
Promotes endothellal
function and
revascularization
IL-6 increases
insulin secretion via
GLP-1

Figure 1 Skeletal muscle is a secretory organ. Leukemia inhibitory factor (LIF), interleukin (IL)-
4, IL-6, IL-7, and IL-15 promote muscle hypertrophy. Myostatin inhibits muscle hypertrophy and
exercise provokes the release of a myostatin inhibitor, follistatin, from the liver. Brain-derived
neurotropic factor (BDNF) and IL-6 are involved in AMP-activated protein kinase (AMPK)-mediated
fat oxidation and IL-6 enhances insulin-stimulated glucose uptake. IL-6 appears to have systemic
effects on the liver and adipose tissue and increases insulin secretion via upregulation of GLP-1.
Insulin-like growth factor-1 (IGF-1) and FGF-2 are involved in bone formation, and follistatin-
related protein 1 improves endothelial function and revascularization of ischemic vessels. Irisin
has a role in “browning” of white adipose tissue. Adapted, with permission, from (172).

Myokines

Myokines Proinflammatory
adipokines
Type 2 diabetes mellitus,
cardiovascular disease, cancer,
osteoporosis

Figure 2 The interplay between adipokines and myokines represents a Yin-Yang balance.
Especially under conditions of obesity, adipose tissue secretes adipokines that contribute to
establish a chronic inflammatory environment, promoting pathological processes such as
atherosclerosis and insulin resistance. Skeletal muscles are capable of producing myokines
that confer some of the health benefits of exercise. Such myokines might counteract the
harmful effects of proinflammatory adipokines. Adapted, with permission, from (172).

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Pro inflammatory Anti inflammatory
IL-6
TNF
IL-1ra
TNF-R IL-10
Sepsis
Anti inflammatory
IL-6
IL-1ra
IL-10
Excercise
Figure 3 Comparison of sepsis-induced verses exercise-induced in-
creases in circulating cytokines. During sepsis, there is a marked and
rapid increase in circulating tumor necrosis factor-alpha (TNF-α), which
is followed by an increase in interleukin-6 (IL-6). In contrast, during ex-
ercise, the marked increase in IL-6 is not preceded by elevated TNF-α.
Adapted, with permission, from (175).
to a handful of neurotrophic factors and hormones, includ-
ing brain-derived neurotropic factor (BDNF), betaendorphins,
serotonin, dopamine, and noradrenaline (124). However, it
is not known how contracting muscles communicate to the
brain and facilitate increased production, action, or signal-
ing of these neurotransmitters. These examples all illustrate
effects of exercise, which may be mediated by one or more
secreted products from the muscle. In the early days, it was
anticipated that the exercise factor would be a simple metabo-
lite or ion released from the active muscle like K+ ion, lactic
acid, adenosine, etc. However, to date, metabolites have not
been identified to mediate muscle-organ cross-talk (7).
In the search for soluble factors that could mediate the
communication between muscle and other organs, we found
it obvious to focus on candidates, previously known from the
immune system. Research that dates back to 1930 demon-
strated that if the pituitary gland was removed in rats, the
thymus would undergo atrophy (175, 220). In 1976, Pelletier
et al. showed that in the dwarf mouse, in which the pitu-
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Muscle as a Secretory Organ
1000
Plasma IL-6 (fold change from rest)
100
10
1
Knee-extensor Bicycling Running Eccentric
Figure 4 Different modes of exercise and the corresponding in-
crease in plasma interleukin-6 (IL-6) levels. Graph is based on 73
exercise trials and represents ∼800 subjects. Each dot indicates one
exercise trial; the corresponding bars represent geometric means with
95% confidence intervals. Although different modes of exercise are as-
sociated with different levels of muscle damage, the increase in plasma
IL-6 levels postexercise is a consistent finding. Modified, with permis-
sion, from (58, 173).
itary function is abnormal, circulating thymic peptide levels
undergo a premature decline (186). These pioneering stud-
ies led to the hypothesis that normal development of the
immune system is dependent on factors produced by the
hypothalamic-pituitary axis. It later appeared that a number of
pituitary hormones, for example, prolactin, growth hormone,
and adrenocorticotropin, may serve as immunomodulatory
factors (63, 99, 175). Initially, cytokines (glycoproteins with
molecular masses of 15,000-30,000) (45) were known for
their immunoregulatory roles. However, other studies demon-
strated that cytokines were involved in complex networks of
communication between the neuroendocrine and the immune
system. It appeared that cytokines were involved in modulat-
ing the secretion from the hypopituitary-hypothalamus axis
and an important neuroendocrine-immune loop was identified
(40, 221) (175).
During the past 20 to 30 years, it has become evident that
exercise induces considerable changes in the immune sys-
tem, especially with regard to the innate immune system, also
known as nonspecific immune system and first line of defense.
Studies of the interactions between exercise and the immune
system have provided unique opportunities to evaluate the
role of the underlying endocrine and cytokine mechanisms
(175, 176).
As with many paradigm-shifting studies, our initial find-
ings that led to the identification of interleukin-6 (IL-6) as a
myokine were somewhat serendipitous. In 1988, we had ini-
tiated systematic studies on the effects of exercise on the im-
mune system (183). This research soon opened a new research
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Muscle as a Secretory Organ
field called “exercise immunology,” leading in 1993 to the
foundation of the International Society of Exercise and Im-
munology. It was while looking for a mechanistic explana-
tion to understand exercise-induced changes in the distribu-
tion and concentrations of lymphocyte subpopulations that we
and others decided to focus on cytokines and their possible
roles as a link between muscle contractions and cellular im-
mune changes (176). This research soon led to the discovery
that exercise provokes an increase in a number of cytokines
(52, 53, 163, 174, 178, 179, 182).
In year 2000, we were able to demonstrate that contract-
ing human skeletal muscle releases significant amounts of
IL-6 into the circulation during prolonged exercise (232).
An accompanying editorial to this publication suggested
that muscle-derived IL-6 could have metabolic roles (66),
a fact soon supported by experimental studies (106, 228).
In a historical context, the identification of muscle as a
cytokine-producing endocrine organ may be regarded as
a breakthrough. The finding that IL-6 was produced by
contracting muscles and released into the blood (232) soon
led to the discovery that muscle-derived cytokines may play
a role in mediating some of the exercise-associated metabolic
changes, as well as the metabolic changes following training
adaptation.
In continuation, we suggested that cytokines or other pep-
tides that are produced, expressed, and released by muscle
fibers and exert either paracrine or endocrine effects should
be classified as “myokines” (170). Thus, although the idea
of an “exercise factor” can be traced back many years, the
identification of skeletal muscle as a myokine-producing or-
gan opens for a whole new field of research. During the past
decade, myocytes have been identified as cells with a high
secretory capacity in parallel with the concept of adipocytes
being major endocrine cells. It appears that muscle cells, here
defined as myoblasts or myocytes, have the capacity to pro-
duce several hundred secreted factors (20, 82, 254).
The fact that skeletal muscle was identified as a cytokine-
producing organ led to studies, showing that muscle-derived
cytokines played a role in mediating not only some of the
exercise-induced immune changes, but also the exercise-
associated metabolic changes (172).
Myokines and Adipokines in a
Yin-Yang Concept
Adipose tissue was initially considered an inert storage com-
partment for triglycerides, not the least due to pioneering
work from the Spiegelman and Flier (38) laboratories in the
mid-1980s, who demonstrated that adipocytes are capable of
releasing a specific secretory protein, called adipsin or com-
plement factor D. Friedman and colleagues later identified
leptin as a fat cell-specific secretory factor, deficient in the
ob/ob mouse and responsible for mediating a hormonal sig-
nal between fat and the brain (258). Since then, adiponectin,
resistin, acylation-stimulating protein, visfatin, and retinol-
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binding protein-4 have been added to the growing list of
adipokines [for review, see (213)]. Notwithstanding the role
of adiponectin (218), most of the factors that are produced by
adipocytes are, however, considered to be proinflammatory,
for example, tumor necrosis factor-alpha (TNF-α), mono-
cyte chemoattractant protein-1, and plasminogen activator
inhibitor type 1, and potentially harmful with regard to the
development of obesity-induced metabolic and cardiovascu-
lar diseases (CVDs) (172). To neutralize the effect of the
proinflammatory adipokines, it is obvious that another organ
or tissue might offer protection and contribute to produce
anti-inflammatory components that could provide a counter-
balance to the proinflammatory factors that are produced by
adipocytes. Given that exercise offers multiple health bene-
fits, it was reasonable to suggest that skeletal muscle might
secrete proteins that could counteract the harmful effects of
the proinflammatory adipokines secreted by adipose tissue in
the obese state (Fig. 6).
The word “myokine” is derived from the Greek words
for “muscle” and “motion” and in 2003, we suggested this
term should be used as a classification for cytokines or other
peptides that are produced, expressed, and released by muscle
fibers and exert endocrine effects (178).
While the word adipokine refers to factors secreted from
adipose tissue, the term “myokine” refers to a protein that
is secreted from myocytes. Characterization of a number of
myokines reveal that skeletal muscles are capable of produc-
ing and releasing proteins that can both communicate with
cells locally within the muscles (autocrine/paracrine) or to
other distant tissues (endocrine).
This review provides an update on some of the muscle-
derived cytokines that have been identified so far.
Myokines
Characteristics of a myokine
r Myokines are cytokines or other peptides that are produced,
expressed, and released by muscle fibers.
r Myokines may exert autocrine, paracrine, or endocrine
effects.
r Myokines may balance and counteract the effects of
adipokines.
r The muscle-cell secretome consists of several hundred se-
creted products.
r Identified myokines include myostatin, leukemia inhibitory
factor (LIF), IL-6, IL-7, BDNF, insulin-like growth factors
(IGF)-1, fibroblast growth factor 2 (FGF-2), FSTL-1, and
irisin.
r Myokines may mediate protective effects of muscular ex-
ercise, with regard to diseases associated with a physically
inactive lifestyle.
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Myostatin
In 1997, Se-Jin Lee’s laboratory identified myostatin, which
appears to be the first discovery of a secreted muscle factor that
fulfills the criteria for a myokine. Myostatin is produced by
skeletal muscle and secreted into the circulation. It is a highly
conserved member of the TGF-β superfamily and myostatin
knockout results in extensive skeletal muscle hypertrophy in
mice (130), cattle, and humans (202).
Myostatin has effects on muscle growth and is also
involved in the modulation of adipose tissue function and
mass (2, 55, 74, 119, 131, 259). Both aerobic exercise and
resistance training in humans and animals attenuate myostatin
expression and myostatin inactivation seems to potentiate the
beneficial effects of endurance exercise on metabolism (3).
Myostatin secretion is enhanced from myotubes derived from
myoblasts isolated from muscle biopsies of obese compared
with nonobese women (88). In addition, patients with type 2
diabetes have higher levels of muscle myostatin mRNA
content than matched control subjects and muscle myostatin
mRNA is correlated with indices of impaired glucose
metabolism and poor fitness (23).
Follistatin represents another member of the TGF-β su-
perfamily. Follistatin is a naturally occurring inhibitor of myo-
statin with regard to its regulatory role in skeletal muscle. Its
presence in plasma is increased with acute exercise. Interest-
ingly, experimental studies show a marked increase in fol-
listatin levels in the liver in response to exercise, suggesting
the existence of a possible muscle-liver cross-talk during and
following exercise (78).
Conclusion
Myostatin has effects on muscle growth and its expression is
regulated by both aerobic exercise and resistance. High levels
of myostatin inhibit muscle growth and vice versa. Myostatin
is negatively regulated by follistatin, which appears to be
released from the liver during acute exercise.
Interleukin-6
While myostatin was the first muscle-derived peptide to fulfill
the criteria for a myokine, the gp130 receptor cytokine IL-6
was the first myokine that was found to be secreted into the
blood stream in response to muscle contractions (175).
Exercise and systemic levels of IL-6
Aerobic exercise provokes a systemic cytokine response, in-
cluding, for example, IL-6, IL-1 receptor antagonist (IL-1ra),
and IL-10. For reviews, see (8, 32, 49, 67, 68, 143, 162, 164,
171, 175, 181, 184, 240, 245, 255) (Fig. 3).
IL-6 was serendipitously discovered as a myokine be-
cause of the observation that it increased in an exponential
fashion proportional to the length of exercise and the amount
of muscle mass engaged in the exercise [for review, see (58)].
It has been consistently demonstrated that the plasma con-
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Muscle as a Secretory Organ
centration of IL-6 increases during muscular exercise (58).
This increase is followed by the appearance of IL-1ra and the
anti-inflammatory cytokine IL-10. In general, the cytokine
response to exercise and sepsis differs with regard to TNF-α.
Thus, the cytokine response to exercise is not preceded by an
increase in plasma-TNF-α.
Following exercise, the basal plasma IL-6 concentration
may increase up to 100-fold, but less dramatic increases are
more frequent (58, 173).
The exercise-induced increase of plasma IL-6 occurs in
an exponential manner (59, 157, 232) and the peak IL-6 level
is reached at the end of the exercise or shortly thereafter
(59, 157, 162). It is the combination of mode, intensity, and
duration of the exercise that determines the magnitude of the
exercise-induced increase of plasma IL-6 (58). IL-6 has pre-
viously been classified as a proinflammatory cytokine. There-
fore, it was first thought that the exercise-induced IL-6 re-
sponse was related to muscle damage (29). However, it has
become evident that eccentric exercise is not associated with a
larger increase in plasma IL-6 than exercise involving concen-
tric “nondamaging” muscle contractions. This finding clearly
demonstrates that muscle damage is not required to provoke
an increase in plasma IL-6 during exercise. As a matter of fact,
eccentric exercise may result in a delayed peak and a much
slower decrease of plasma IL-6 during recovery (81,125,249).
The amount of IL-6 produced is correlated to the amount
of muscle mass engaged in the exercise. Muscles of the upper
extremities may be insufficient to increase plasma IL-6 above
preexercise level (18, 86, 154). In contrast, running—which
involves several large muscle groups—is the mode of exercise
during which the most dramatic plasma IL-6 increases have
been observed (Fig. 4).
In a review by C. Fischer (100), he shows that exercise
duration is the single most important factor determining the
postexercise plasma IL-6 amplitude and that 50% of the vari-
ation in plasma IL-6 following exercise can be explained by
exercise duration alone (P < 10−12 ) (58).
Based on the log-log linear relationship between time and
fold increase of plasma IL-6, a tenfold increase of plasma IL-
6 requires exercise for 1.9 h (CI 1.6-2.9 h, P < 0.0001), while
a 100-fold increase of plasma IL-6 requires exercise lasting
6.0 h (CI 4.5-8.1 h, P < 0.0001) (Fig. 5).
IL-6 has been shown to be synthesized and released from
contracting muscles alone and not from resting muscles ex-
posed to the same hormonal changes (100, 232), demonstrat-
ing that circulating systemic factors cannot explain why con-
tracting muscles synthesize and release IL-6. Of note, the
increase of IL-6 in the circulation occurs during exercise with-
out any sign of muscle damage (58). Until the beginning of
this millennium, it was commonly thought that the increase
in IL-6 during exercise was a consequence of an immune re-
sponse due to local damage in the working muscles (151) and
it was hypothesized that macrophages were responsible for
this increase (140). However, an early study (239) demon-
strated that IL-6 mRNA in monocytes did not increase as a
result of exercise. Further work confirmed this finding at the
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Linear regression
1000 Plasma IL-6 (fold change) = antilog10[1.030 · log10[duration (h)] + 0.695]
n = 74 exercise trials (~800 subjects)

Plasma IL-6 (fold increase from rest)

2
R = 0.51
-12
P < 10

100
Knee-extensor
Bicycling
10 Running
Eccentric
Regression

0.1
0.1 1 10 100
Exercise duration (h)

Figure 5 The overall log10 -log10 linear relation (straight solid line) between
exercise duration and increase in plasma interleukin-6 (IL-6) (fold change from
preexercise level) indicates that 51% of the variation in fold plasma IL-6 increase
may be explained by the duration of exercise. Modified, with permission, from
(58).

protein level (225, 227). In addition, the liver clears, rather adaptation attenuate the exercise-sensitive increase in IL-6
than secretes, IL-6 during exercise (51). plasma concentration (60, 169).
The finding that the nuclear transcription rate for IL-6 and It has been shown that skeletal muscle cells are capable
the IL-6mRNA levels were rapidly and markedly increased of producing IL-6 in response to various stimuli such as incu-
after the onset of exercise (106, 231) suggested that a factor bation with lipopolysaccharide, reactive oxygen species, and
associated with contraction was responsible for the increase inflammatory cytokines. In response to the latter stimuli, the
in IL-6 transcriptional rate within the nuclei from myocytes. upstream signaling events that lead to the induction of IL-6
Febbraio’s group found further evidence that contracting mus- have been well categorized. As mentioned above, human
cle fibers themselves were a source of IL-6 mRNA and pro- skeletal muscle is unique as it can produce IL-6 in response to
tein. Such data were achieved by analysis of biopsies from contraction in the absence of inflammation (52) and notewor-
the human vastus lateralis using in situ hybridization and im- thy in a TNF-independent fashion (104). Thereby, muscle-
munohistochemistry techniques (87). derived IL-6 is being linked to metabolism rather than in-
The microdialysis technique indicated that the concentra- flammation. Muscle-glycogen level is a determining factor as
tion of IL-6 within the contracting skeletal muscle could be 5- both intramuscular IL-6 mRNA expression (106) and protein
to 100-fold higher than the levels found in the circulation and release (228) are exacerbated when intramuscular glycogen
that IL-6 appears to accumulate within the contracting muscle is compromised, suggesting that IL-6 is somehow regulated
fibers as well as in the interstitium during exercise (203). by glycogen content.
Measurement of arteriovenous IL-6 concentrations and Several studies have shown that glucose ingestion dur-
blood flow across the leg has demonstrated that IL-6 is re- ing exercise attenuates the exercise-induced increase in
leased in relatively high quantities into the circulation from plasma-IL-6 (83, 114, 116-118, 140, 146-148, 151), but not
the exercising leg (232). IL-6 mRNA expression within the contracting muscle itself
A number of studies have confirmed that IL-6 is indeed (54, 140, 151, 226). Contraction may lead to IL-6 gene tran-
produced by muscle cells. Thus, IL-6 has been shown to be scription via calcium (Ca2+ ) being released from the sar-
expressed by human myoblasts (15,41) and by human cultured coplasmic reticulum to activate IL-6 through activation of
myotubes (104). In addition, IL-6 is produced by growing nuclear factor of activated T (NFAT) cells (93). In human
murine myofibers and associated muscle stem cells (satellite skeletal muscle cell cultures, IL-6 mRNA increases time and
cells) (217) and released from human primary muscle cell dose dependently with ionomycin stimulation, an effect that
cultures from healthy individuals (72, 79) and from patients is blunted by the presence of the calcineurin-inhibitor Cy-
with type 2 diabetes (72, 211). closporin A. In contrast, TNF-α gene expression is decreased
in response to ionomycin treatment, demonstrating that IL-
6 and TNF-α are regulated differentially in skeletal muscle
IL-6 is an energy sensor cells in response to a Ca2+ stimulus (104).
Muscle-derived IL-6 works as an exercise sensor (89, 169, Regular exercise leads to a number of physiological, adap-
179, 206). Thus, enhanced glucose availability and training tive responses. These include increased levels of basal skeletal

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Comprehensive Physiology Muscle as a Secretory Organ

Muscular expression of IL-6R

IL-6

Concentration muscle glycogen

Concentration IL-6
IL-6
Gly
cog
en

Gl
yc
og
en IL-6
G
ly
co
ge
n

Exercise Exercise Exercise

Time

Figure 6 The figure presents a model on how interleukin-6 (IL-6) is regulated

in response to training adaptation. Regular exercise leads to an enhancement
of glycogen synthase and a trained muscle will consequently store more mus-
cle glycogen. During acute exercise, the untrained muscle is highly dependent
on glycogen as substrate, whereas training leads to an enhancement of beta-
oxidating enzymes and an enhanced capability to oxidize fat and hence to use
fat as substrate during exercise. This means that the trained muscle uses less
glycogen during work. The activation of muscle-IL-6 is glycogen dependent.
At conditions with low muscle glycogen, the transcription rate of IL-6 is faster
and relatively more IL-6 is produced at the same relative work compared to
conditions with high muscle glycogen. Thus, the acute plasma IL-6 response is
lower in a trained versus an untrained subject. The mechanisms whereby basal
plasma-IL-6 is decreased by training and whereby the muscular expression of
IL-6 receptors (IL-6R) is enhanced are not fully understood. However, it appears
that a trained muscle may be more sensitive to IL-6. Adapted, with permission,
from (175).

muscle glycogen content, enhanced activity of key enzymes
involved in the β-oxidation, increased sensitivity of adipose
tissue to epinephrine-stimulated lipolysis, and increased ca-
pacity to oxidize fat. Consequently, the trained skeletal muscle
is less dependent on plasma glucose and muscle glycogen as
substrates during exercise (175, 190).
Several observational studies have reported a negative as-
sociation between the amount of regular physical activity and
the resting plasma IL-6 levels: the more physically active, the
lower basal plasma IL-6 (58). On the other hand, high plasma
levels of IL-6 are closely associated with physical inactivity
and the metabolic syndrome. Intervention studies show that
basal levels of IL-6 are reduced after training (58). It also
appears that the exercise-induced increase in plasma IL-6 and
muscular IL-6 mRNA is less pronounced in trained versus un-
trained individuals (60). However, while plasma-IL-6 appears
to be down regulated by training, the muscular expression of
the IL-6 receptor (IL-6R) is unregulated. Moreover, the basal
IL-6R mRNA content in trained skeletal muscle is increased
compared to untrained conditions (105), suggesting that the
sensitivity to IL-6 is increased (Fig. 6).
We recently reported that insulin-resistant individuals
demonstrated IL-6 resistance (211). Accordingly, we suspect
that muscle disuse may lead to IL-6 resistance. The elevated
circulating levels of IL-6 that accompany obesity and physi-
cal inactivity may represent a compensatory mechanism. This
would be in line with the well-known facts that insulin resis-
tance is accompanied by hyperinsulinemia and that chronic
high circulating levels of leptin may reflect leptin resistance.
IL-6—a role in glucose and lipid metabolism
IL-6 has been shown to enhance glucose production both in
vitro and in vivo (172) and cytokine signaling through AMP-
activated protein kinase (AMPK) appears to play a major role
(234). Several studies have shown that IL-6 enhances glu-
cose uptake and increases intramyocellular (28, 33, 189) or
whole body (241) fatty acid oxidation via an effect on AMPK

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(33, 101). It appears that IL-6 activates AMPK in skeletal
muscle by increasing the concentration of cAMP, and sec-
ondarily, the AMP:ATP ratio (107). IL-6 mediates signaling
through the gp130 receptor and exhibits many “leptin-like”
actions (133, 233, 234, 246). In healthy skeletal muscle, and
not least in humans, the IL-6-induced activation of AMPK
appears to override the IL-6-induced activation of suppressor
of cytokine signaling (SOCS)-3. Accordingly, IL-6 knockout
mice develop mature onset obesity and glucose intolerance
(243), supporting the notion that IL-6 may exert beneficial
effects on metabolism. IL-6 increases insulin-stimulated glu-
cose uptake in vitro in healthy individuals, while infusion
of recombinant human (rh) IL-6 into healthy humans during
a hyperinsulinemic, euglycemic clamp increases the glucose
infusion rate without affecting the total suppression of en-
dogenous glucose production (EGP) (33).
IL-6 can be classified as a myokine with an endocrinolog-
ical activity since it contributes to hepatic glucose production
during exercise (50). However, it is not clear how the tightly
controlled production and clearance of glucose during mus-
cular work are regulated. It is possible that an unidentified
“work factor” exists that influences the contraction-induced
increase in EGP. We infused rhIL-6 at physiological concen-
trations into resting human subjects. Acute administration of
rhIL-6 had no effect on whole-body glucose disposal, glu-
cose uptake or EGP (123, 189, 230). In contrast, we found
that IL-6 contributed to the contraction-induced increase in
EGP. Healthy men performed 2 h of bicycle exercise on three
separate occasions: (i) at a relatively high intensity (HI) and
(ii) at a low intensity with (LO + IL-6) or without (LO) an
infusion of rhIL-6 that mimicked the circulating concentra-
tion of IL-6 observed during HI exercise. This study revealed
a direct muscle-liver “cross-talk” (50).
Infusion of rhIL-6 into healthy humans caused an increase
in lipolysis in the absence of hypertriglyceridaemia or changes
in catecholamines, glucagon, insulin, or any adverse effects in
healthy individuals (123, 189, 241). These findings combined
with cell culture experiments showed that IL-6 had direct
effects on both lipolysis and fat oxidation and identify IL-6
as a lipolytic factor (189). In a recent study, we were able
to distinguish between lipolysis in muscle and adipose tissue
and found that IL-6 primarily stimulated lipolysis in skeletal
muscle, whereas abdominal adipose tissue was unaffected
(251).
Ellingsgaard et al. found that the pancreatic alpha cell is a
primary target of IL-6 action (47) and that IL-6 promotes al-
pha cell proliferation and inhibits apoptosis. They showed that
in response to a high-fat diet, alpha cell mass expands in an
IL-6-dependent manner and that whole-body IL-6 knockout
mice with no alpha cell expansion showed increased glycemia
after feeding caused by impaired insulin secretion. These find-
ings show that alpha cell expansion in response to a high-fat
diet may be required for functional beta cell compensation
and that systemically increased IL-6 abundance induced by
a high-fat diet is an adaptive response necessary to maintain
proper insulin secretion and glucose homeostasis. In another
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study, Ellingsgaard et al. demonstrated the existence of an
adipose tissue and skeletal muscle enteroendocrine-islet axis.
This cross-talk between insulin-sensitive tissues and insulin-
producing cells was shown to be mediated through IL-6 acting
on L cells and alpha cells to promote Glucagon-like peptide-
1 (GLP-1) secretion and production, thereby allowing for an
adaptation to increased insulin demand during obesity and im-
proved beta cell function in response to physical training (48).
Conclusion
IL-6 is the myokine prototype (Fig. 7). The systemic level
of IL-6 increases markedly with exercise and skeletal muscle
is the main source of origin. Muscle contractions lead to the
production and release into the circulation of IL-6, which
appears to have numerous biological effects, including effects
on glucose and fat metabolism. In addition, IL-6 has a role
in myogenesis and mediates anti-inflammatory effects, see
below.
BDNF
Neurotrophins are a family of structurally related growth
factors, including BDNF, which exert many of their effects
on neurons primarily through Trk receptor tyrosine kinases.
Among these, BDNF and its receptor TrkB are the ones most
widely and abundantly expressed in the brain (97). However,
several studies verify that skeletal muscle is also capable of
expressing BDNF (165, 166, 177).
Studies in rodents demonstrate that both exercise and elec-
trical stimulation (and contraction) of skeletal muscle lead to
an induction of BNDF expression in muscle (39,70,128,216).
Several studies have also reported that exercise induces
an expression of BDNF in skeletal muscle. For example, Co-
pray et al. (39) found that intense contraction of the soleus
muscle in both normal and diabetic rats caused an increase
in the expression of BDNF. In addition, ultrastructural stud-
ies from these same authors found that BDNF expression was
localized within muscle fibers and activated satellite cells. Im-
portantly, no expression of BDNF was observed in Schwann
cells or fibroblasts, suggesting that the localization of BDNF
was defined within the muscle fibers.
In other studies, Gomez-Pinilla et al. (70) found that
BDNF mRNA and protein levels in rodents increased in the
soleus muscle after 3 and 7 days of exercise. Interestingly, fol-
lowing paralysis of the soleus muscle, BDNF mRNA levels
were reduced, demonstrating that active muscle contraction
is important in modulating BDNF levels in muscle. In addi-
tion, BDNF appears to play a role in the development and
differentiation of myoblasts and muscle fibers (134, 138).
It is well known that BDNF increases in brain tissue in re-
sponse to acute exercise and exercise training and may account
for the effect of exercise in the protection against neurodegen-
erative diseases such as dementia (128). We studied whether
human skeletal muscle would produce BDNF in response
to exercise (128) and found that BDNF mRNA and protein
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Comprehensive Physiology Muscle as a Secretory Organ

IL-6

IL-6Rα/gp130Rβ

Pl3-K p-STAT3

p-Akt p-AMPK Blood vessel

Glucose uptake Fat oxidation IL-6

Liver

IL-6
Increased hepatic glucose
Contraction production during exercise

IL-6 IL-6

IL-6 IL-6
IL-6
IL-6
Adipose tissue

IL-6

Increased lipolysis

Figure 7 Biological role of contraction-induced interleukin-6 (IL-6). Skeletal muscle expresses and releases myokines
into the circulation. In response to muscle contractions, both type I and type II muscle fibers express the myokine IL-
6, which subsequently exerts its effects both locally within the muscle (e.g., through activation of AMPK) and—when
released into the circulation—peripherally in several organs in a hormone-like fashion. Specifically in skeletal muscle,
IL-6 acts in an autocrine or paracrine manner to signal through a gp130Rβ/IL-6Rα homodimer resulting in activation
of AMP-kinase and/or PI3-kinase to increase glucose uptake and fat oxidation. IL-6 is also known to increase hepatic
glucose production during exercise or lipolysis in adipose tissue. Modified, with permission, from (173).

expression were modestly increased in human skeletal muscle
after exercise. However, muscle-derived BDNF appeared not
to be released into the circulation. BDNF mRNA and protein
expression were clearly increased in muscle cells that were
electrically stimulated. Interestingly, BDNF increased phos-
phorylation of AMPK and Acetyl-CoA carboxylase (ACC)
and enhanced fat oxidation both in vitro and ex vivo. Thus,
we were able to identify BDNF as a novel contraction-
induced muscle cell-derived protein that may increase fat
oxidation in skeletal muscle in an AMPK-dependent fash-
ion (165, 166, 177). Other studies consistently demonstrate
that muscle-derived BDNF and other neurotrophins serve as
important regulators of the maintenance, function, and regen-
eration of skeletal muscle fibers. Thus, BDNF is an injury-
related factor that is involved in the survival and function of
innervating motorneurons [reviewed in (210)].
Conclusion
Taken together, BDNF is a protein produced in skeletal mus-
cle cells, which is increased by contraction to enhance fat
oxidation in an AMPK-dependent fashion, most probably by
acting in an autocrine and/or paracrine manner within skele-
tal muscle. In addition, muscle-derived BDNF plays a role
in muscle repair, regeneration, and differentiation. Thus, in
addition to its well-known role in neurobiology, BDNF can
be identified as a myokine that plays a role in peripheral
metabolism, myogenesis, and muscle regeneration.
Interleukin-7
Interleukin-7 (IL-7) is a cytokine that is required for T and
B cell development, whereas possible biological functions of
IL-7 in nonimmune cells have not been explored. Recently,
Haugen et al. identified IL-7 as a myokine (79).
IL-7 mRNA and IL-7 protein were detected in conditioned
media from primary cultures of human myotubes as well
as inside the myotubes. The amount of IL-7 in the medium
increased with incubation time (79).
Incubation with recombinant IL-7 during differentia-
tion induced a reduction in mRNA for the terminal myo-
genic markers myosin heavy chain (MHC) 2 and myogenin
(MYOG). This finding suggests that IL-7 may act on satellite
cells and may be involved in myogenesis. The authors also
demonstrated that the muscular expression of IL-7 mRNA
was increased several fold in resting musculus vastus lateralis

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and musculus trapezius biopsies taken from male individuals
undergoing a strength training program.
Conclusion
IL-7 has recently been identified as a myokine involved in
myogenesis. Its expression in resting skeletal muscle is in-
creased with training adaptation.
Interleukin-8
Interleukin-8 (IL-8) belongs to the CXC family of
chemokines. The CXC nomenclature relates to the presence
of two conserved cysteine residues at the amino terminus sep-
arated by one amino acid. IL-8 belongs to a subdivision of
CXC-chemokines, which has an amino acid sequence Glu-
Leu-Arg (ELR) preceding the first conserved cysteine amino
acid residue in the primary structure of these proteins (10).
Murine CXCL-1 shares the highest sequence homology with
human CXCL-1, but it is often mentioned as the functional
homolog to human IL-8 (205).
CXCL-1 and IL-8 possess neutrophil chemoattractant ac-
tivity. In addition, they are involved in the processes of an-
giogenesis (122). The ability of IL-8 to induce angiogenesis
is distinct from its ability to induce inflammation (103). IL-
8 associates with the CXC receptors 1 and 2 (CXCR1 and
CXCR2) (17). CXCR2 is expressed by human microvascular
endothelial cells and is the receptor responsible for IL-8-
induced angiogenesis (1).
The production of different chemokines in the ELR+ CXC
family has been shown to be induced by IL-6 (237). There-
fore, we studied the role of exercise and IL-6 in the regulation
of murine CXCL-1 (185). Following a single bout of exercise,
CXCL-1 increased in serum, muscle, and liver. The exercise-
induced regulation of liver CXCL-1 mRNA expression was
completely blunted in IL-6 knockout mice. When IL-6 was
overexpressed in murine muscles, we found a marked in-
crease in serum CXCL-1 and liver CXCL-1 mRNA expres-
sion. These data demonstrate a robust muscle-liver cross-talk
during exercise in which exercise-induced IL-6 production
stimulates the liver to produce CXCL-1. The study found a
higher expression of CXCL-1 in liver compared to muscle.
However, it has clearly been demonstrated that muscular IL-8
mRNA levels are enhanced by exercise (147) and that IL-8 is
released by human primary cultured myotubes (79).
The plasma concentration of IL-8 increases in response to
exhaustive exercise such as running, which involves eccentric
muscle contractions (148-150, 158, 236). In addition, a slight
increase in IL-8 plasma concentration has been reported dur-
ing intense cycle ergometry (139).
The possibility of contracting skeletal muscle express-
ing IL-8 has received some attention. In a pioneering study
by Nieman and co-workers, a several-fold increase in IL-8
mRNA was found in skeletal muscle biopsies from subjects
having completed a 3-h-treadmill-run concomitantly with in-
creased plasma levels of IL-8 (148).
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Conclusion
IL-8 and CXCL-1 increase in contracting skeletal muscle and
IL-8 is released from human muscle cells in vitro. The phys-
iological function of IL-8 within the muscle is, however, still
unknown. The main part of the systemic increase in IL-8 as
seen during exercise with an eccentric component is most
likely due to an inflammatory response. However, muscle-
derived IL-8 is likely to occur locally and exert its effect in
an autocrine or paracrine fashion. A more likely function of
muscle-derived IL-8 is to stimulate angiogenesis in skele-
tal muscle. IL-8 associates with the CXC receptor 1 and 2
(CXCR1 and CXCR2) and IL-8 has been proven to play a
direct role in endochelial cell survival, proliferation, and an-
giogenesis (108, 115).
Interleukin-15
IL-15 is a 14 kDa cytokine. It belongs to the IL-2 superfamily
and was originally isolated on the basis of its ability to
support natural killer T-lymphocyte proliferation. IL-15 is
expressed at the mRNA level in a variety of nonlymphoid
tissues, with particularly high expressions in skeletal muscle
and placenta. IL-15 is also expressed abundantly in cardiac
muscle, lung, liver, kidney, brain, and pancreas (71). The
regulatory role of muscle contraction with regard to IL-15 re-
mains unclear. Nieman et al. found that muscle IL-15mRNA
levels were unchanged immediately after a 3-h run (148),
and Ostrowski et al. found that plasma IL-15 (measured up
to 6 h into recovery) did not change in response to 2.5 h of
treadmill running (157). Skeletal muscle IL-15 mRNA levels,
measured immediately after a 2-h weight training bout, did
not differ from baseline (146), whereas in one study plasma
IL-15 protein increased immediately after acute resistance
exercise (201). We demonstrated that IL-15 mRNA levels
are unregulated in human skeletal muscle following a bout
of strength training (142).
IL-15 has been identified as an anabolic factor that is
highly expressed in skeletal muscle (71). Furthermore, IL-15
has been suggested to play a role in muscle-adipose tissue
interaction (6). In human skeletal myogenic cultures, IL-15
induces an increase in the accumulation of the protein MHC
in differentiated muscle cells. This suggests that IL-15 is an
anabolic factor in muscle growth (61). Moreover, IL-15 stim-
ulates myogenic differentiation independently of IGFs (198)
and in contrast to IGF-1, IL-15 has effects on fully differen-
tiated myoblasts (196). The ability of IL-15 to antagonize the
enhanced muscle protein breakdown as demonstrated in an in
vivo cancer cachexia model points to the potential therapeutic
effect of IL-15 (31, 57).
Interestingly, while IL-15 has been reliably demonstrated
to have anabolic effects on skeletal muscle in vitro and in vivo,
IL-15 seems also to play a role in reducing adipose tissue
mass, as IL-15 decreases lipid deposition in preadipocytes and
decreases the mass of white adipose tissue (WAT) (30, 199).
When IL-15 was administered to adult rats for 7 days,
it resulted in a 33% decrease in WAT mass (30). The tissue
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response to IL-15 was related to the amount of IL-15/IL-15
receptor complex expression, suggesting a direct action of IL-
15 on adipose tissue (5). IL-15 mRNA expression has been
examined in both 3T3-L1 adipogenic cells and C2C12 murine
skeletal myogenic cells. Quantitative real-time PCR indicated
that IL-15 mRNA was expressed by C2C12 skeletal myogenic
cells and was unregulated more than tenfold in differentiated
skeletal myotubes compared to undifferentiated myoblasts.
In contrast, 3T3-L1 cells expressed little or no IL-15 mRNA
on either the undifferentiated preadipocyte or differentiated
adipocyte stages (199). These findings provide support for
the hypothesis that IL-15 may function in a muscle-to-fat
endocrine axis that modulates fat; lean body composition and
insulin sensitivity.
The effect of IL-15 on adipocyte differentiation was ana-
lyzed using the 3T3-L1 preadipose cell line. The data showed
that IL-15 tends to reduce the rate of adipocyte prolifera-
tion, induces apoptosis, and partially stops differentiation.
The signaling molecules behind these actions of the cytokine
on adipose cells are: p42/p44 MAPK (which seem to be as-
sociated with the reduced rate of proliferation induced by the
cytokine), signal transducer and activator of transcription 5
(STAT5) (which is related to the actions of IL-15 on differ-
entiation), and stress-activated protein kinase (SAPK)/c-Jun
N-terminal kinase (JNK) (which are related to the increased
apoptosis induced by IL-15). Altogether, results from cell
culture studies suggest that IL-15 is involved in the regula-
tion of adipose tissue size (62). In support of these in vitro
studies, a negative association was found in humans between
plasma IL-15 on one hand and total fat mass, trunk fat mass,
and percent fat mass, on the other (141). A similar finding
was reported by Barra et al. who observed that obese human
subjects exhibited lower circulating IL-15 levels than lean
subjects (14). This could indicate that IL-15 was involved in
exerting an antiobesity effect.
However, Christiansen et al. reported decreased circulat-
ing IL-15 concentrations following a diet-induced weight loss
in obese human subjects (37).
IL-15KO mice have higher amounts of body fat than con-
trol mice (14) whereas transgenic mice with elevated circulat-
ing levels of IL-15 due to a skeletal muscle-specific promoter
have lower levels of body fat than controls and are resistant
to diet-induced obesity (197). In the latter study by Quinn
et al., it was shown that mice that expressed high intramus-
cular levels of IL-15 without concomitant increased levels of
serum IL-15 levels showed no differences in adiposity com-
pared to controls. The data suggest that IL-15 have to be
secreted into the circulation to exert its effects on adipose
tissue.
IL-15 has also been introduced into rodents by injection
of recombinant IL-15 protein, by adenoviral expression vec-
tors (14, 30) and by DNA electrotransfer into skeletal muscle
(141). The findings from these studies were that IL-15 ad-
ministration reduces fat mass by as much as 30% in normal
rodents and by 10% in obese rodents without an effect on
food consumption.
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IL-15 injection inhibits fat deposition in both wild-type
and ob/ob mice (5). Physical inactivity leads to loss of mus-
cle mass and accumulation of visceral fat (155) and there are
some pieces of evidence pointing at IL-15 somehow being
involved in the regulation of abdominal adiposity. In humans,
we found a negative association between plasma IL-15 con-
centration and trunk fat mass, but not limb fat mass. In support,
we demonstrated a decrease in visceral fat mass, but not sub-
cutaneous fat mass, when IL-15 was overexpressed in murine
muscle (141).
Both humans and laboratory mice exhibit detectable lev-
els of IL-15 in the circulation (195). The possibility, therefore,
exists that IL-15 may exert endocrine (as well as paracrine)
effects on cell types that do not themselves express IL-15.
Still, at present it is unknown from which tissues the circu-
lating IL-15 originates. Skeletal muscles express high levels
of IL-15 and it has been suggested that IL-15 functions as a
myokine that exerts positive effects on body composition via
an endocrine mechanism (30, 141, 165, 199). Although IL-15
appears to play a role in muscle-fat cross-talk, controversy
exists with regard to whether IL-15 should be classified as a
true myokine (195).
Conclusion
IL-15 has been identified as an anabolic factor that is constitu-
tively expressed by skeletal muscle and regulated by strength
training. While IL-15 has solid anabolic effects, it also seems
to play a role in reducing adipose tissue mass and it is therefore
suggested that IL-15 may play a role in muscle-fat cross-talk.
We suggest that muscle-derived IL-15 should be classified as
a potential myokine.
LIF
LIF is a newly discovered myokine (26). Nevertheless, LIF
was identified already in 1988 as a protein secreted from as-
cites tumor cells (84). The initial observed function of LIF
was its ability to induce terminal differentiation of myeloid
leukemic cells (hence its name LIF). Today it is known that
LIF has a wide array of actions, including acting as a stim-
ulus for platelet formation, proliferation of hematopoietic
cells, bone formation, neural survival and formation, mus-
cle satellite cell proliferation, and acute phase production by
hepatocytes (132). LIF is a long chain four α-helix bundle
cytokine, which is highly glycosylated and may be present
with a weight of 38 to 67 kDa that can be deglycosylated to
∼20 kDa (80, 85, 215). The effects of LIF are initiated when
LIF binds the specific LIF receptor and gp130 (64), which
leads to phosphorylation and thereby activation of janus ki-
nase (JAK) and the STAT (44, 235). This further results in
expression of SOCS-3, which negatively regulates LIF sig-
naling at the receptor level (44). Several tissues, including
skeletal muscle, express LIF. Hence, LIF is constitutively ex-
pressed at a low level in type 1 muscle fibers (102, 208) and
is implicated in conditions affecting skeletal muscle growth
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and regeneration (73, 102, 208, 223). LIF protein expression
is augmented in mechanically overloaded rat plantaris mus-
cle and in denervated rat muscle (208, 209), thus endogenous
LIF production is modulated by factors influencing muscle
activity. Furthermore, LIF restores the hypertrophic response
to increased loading in LIF (-/-) mice, and in that respect LIF
has been denoted as an important factor in skeletal muscle
hypertrophy (223).
Another, but perhaps related function of LIF is the potency
to induce myoblast proliferation and inhibit differentiation
of myoblasts into multinucleated myotubes (9, 44, 222, 235).
Consequently, LIF seems to affect intact skeletal muscle in
vivo as well as isolated muscle cell cultures in vitro. Seeing
that LIF is produced by skeletal muscle and affects intact mus-
cle as well as isolated muscle cells, we hypothesized that LIF
would be a myokine (175). Although the LIF peptide contains
a secretory amino acid sequence specifying that LIF be di-
rected out of the cell in which the protein is synthesized (85)
no studies had investigated whether LIF is actually secreted
from muscle cells or from intact skeletal muscle. We, there-
fore, undertook a study to determine the potential of LIF as a
secreted myokine. First, we isolated and propagated satellite
cells from muscle biopsies obtained from healthy men, as pre-
viously described (26), and examined whether the cells could
produce and secrete LIF into the cell media. We observed an
accumulation of LIF in the cell media, indicating that LIF
was produced by cultured muscle cells and secreted sponta-
neously. Thus, LIF was not stored within the cells. Secondly,
we used the electrotransfer technique described previously
(141) to overexpress LIF in m. tibialis of mice and assessed
the abundance of LIF in serum. Whereas LIF was undetectable
in the control mice, which had saline injected into musculus
tibialis (m. tibialis), the mice electrotransferred with LIF in
m. tibialis demonstrated high LIF plasma levels 48 h after the
electrotransfer, indicating that LIF was effectively secreted
from the intact mouse muscle. Hence, we concluded that LIF
is a muscle-expressed protein released from cultured muscle
cells in vitro and intact mouse muscle in vivo.
In a study by Broholm et al., it was found that aerobic
exercise induces expression of LIF in human skeletal muscle
(26). The study showed that aerobic exercise and concentric
muscle contractions regulate muscular LIF mRNA expres-
sion in humans. With regard to the molecular mechanism
responsible for the increase in LIF in relation to exercise, it
was shown that human muscle cells that are stimulated with
the Ca2+ ionophore, ionomycin, increase their expression of
both LIF mRNA and protein (26). Thus, oscillations in Ca2+
concentration may be the signal conveying neuromuscular ac-
tivity into changes in the transcription of the LIF gene during
muscle contractions. Since the human LIF promoter contains
three putative (NFAT) cells binding sites (11) the calcineurin-
NFAT pathway could represent a possible mechanism for LIF
gene activation by Ca2+ in myocytes. IL-6 is also regulated
by Ca2+ , possibly through calcineurin (12) thereby suggesting
that Ca2+ oscillations constitute a common signal to increase
transcription of myokines during exercise.
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Although muscular LIF mRNA levels appear responsive
to different types of exercise, LIF protein levels remain un-
altered (26), suggesting that repetitive bouts of exercise are
necessary to induce accumulation of LIF protein in skele-
tal muscle, although the latter suggestion needs to be ad-
dressed in long-term endurance training studies. In addition,
muscle-derived LIF seems to be muscle specific as LIF was
undetectable in plasma in human subjects following bicycle
exercise (26). Besides detection limitations, it is possible that
LIF is secreted to the interstitial space between muscle fibers
and never reaches the circulation. This suggests that LIF does
not function as a systemic myokine, as does for example IL-
6, but is more likely to affect skeletal muscle in an autocrine
and/or a paracrine fashion.
Austin and co-workers demonstrated that LIF stimulates
myoblast proliferation in culture (9) thereby showing that LIF
functions as a mitogenic growth factor when added experi-
mentally to muscle precursor cells in vitro. To date, differ-
ent groups have confirmed this finding and shown that LIF
induces satellite cell and myoblast proliferation, while pre-
venting premature differentiation, by activating a signaling
cascade involving JAK1, STAT1, and STAT3 (4,44,222,235).
In line with this, the specific LIF receptor is primarily ex-
pressed by satellite cells and not by mature muscle fibers
(102). Muscle satellite cells start to form at the late stage of
vertebrate embryo development (42). In the adult muscle, the
satellite cells are quiescent and located beneath the basal lam-
ina and the plasma membrane (242). However, in response
to muscle injury or exercise the normally quiescent cells be-
come activated, re-enter the cell cycle and start to proliferate.
Later in the process, the cells irreversibly withdraw from the
cell cycle and fuse with preexisting myofibers (42). There is
increasing evidence that muscle adaptation and hypertrophy
depend on the addition of new myonuclei by way of prolifer-
ation and further fusion of satellite cells to the adult muscle
fibers (42). Hence, LIF may be involved in muscle adaptation
to exercise through its potent effect on muscle satellite cells.
Indeed, Spangenburg and co-workers showed that LIF (-/-)
mice were unable to enlarge their muscle size in response
to increased muscle load. However, the hypertrophic muscle
response was restored when the mice were given systemic
treatments with LIF. Accordingly, the authors suggested that
LIF was an important factor in muscle hypertrophy (223).
Muscle regeneration is another process relying on activation
and proliferation of satellite cells (42), and in this regard LIF
also demonstrates in vivo effects. LIF stimulates muscle re-
generation in mice suffering from muscle dystrophy (112),
and LIF (-/-) mice show reduced muscle regeneration follow-
ing muscle injury (109), thereby demonstrating that LIF is
directly involved in regeneration of skeletal muscle. Thus, the
possibility exists that the proliferative effects of LIF on satel-
lite cells are closely linked to the role of LIF in muscle hyper-
trophy and regeneration. Depending on the type and duration
of exercise, muscle adaptation may involve processes such
as muscle growth and muscle regeneration. LIF is produced
during exercise and might contribute to muscle adaptation
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Comprehensive Physiology Muscle as a Secretory Organ

following exercise by stimulating muscle satellite cell pro- comitantly led to an increase in total body energy expenditure
liferation, a process important for muscle hypertrophy and and modest improvements in glucose intolerance.
regeneration. In consequence, we hypothesize that the pri-
mary function of LIF, as a contraction-induced myokine, is Conclusion
that of a mitogenic growth factor affecting nearby satellite
cells in a paracrine fashion (27). Irisin was recently identified as a myokine, which is regulated
by exercise and plays a role in driwing white fat cells into
“brite” cells with a brown-fat-like phenotype (168).
Conclusion
LIF is a newly discovered myokine, which is induced in skele- Erythropoietin
tal muscle following exercise and affects satellite cells, muscle
Erythropoietin (EPO) is well known as a kidney-produced
growth, and regeneration.
hormone with distinct effects on erythropoiesis. However,
EPO may also be classified as a nonimmunologic cytokine,
Irisin which belongs to the IL-2 subfamily and recent studies sug-
gest that EPO should also be classified as a myokine. We
Irisin was recently identified as a new myokine, which is re-
overexpressed EPO in murine skeletal muscles by gene elec-
leased into the circulation during exercise. Irisin drives white
trotransfer. This resulted in a 100-fold increase in serum
fat cells into “brite” cells; white fat cells with a brown-fat-like
EPO and concomitant increases in hemoglobin levels. After
phenotype (21) (Fig. 8).
12 weeks, EPO expression resulted in a 23% weight reduc-
Brown fat generates heat via the mitochondrial uncoupling
tion in EPO transfected obese mice and a reduction in adipose
protein UCP1 and it has been suggested that there are two
tissue mass. EPO expression also induced a 14% increase in
distinct types of brown fat: classical brown fat derived from a
muscle volume and a 25% increase in vascularization of the
myf-5 cellular lineage and UCP1-positive cells that emerge in
EPO transfected muscle. EPO overexpression was accompa-
white fat from a non-myf-5 lineage. It was recently reported
nied by an improvement in fasting insulin levels and glucose
that so-called “beige” cells could be isolated from murine
tolerance in the high-fat fed mice. In addition, muscular fat
white fat depots. Beige cells resemble white fat cells in having
oxidation was increased 1.8-fold in both the EPO transfected
extremely low basal expression of UCP1, but, like classical
and the contralateral muscle. Thus, it appeared that supra-
brown fat, they respond to cyclic AMP stimulation with high
physiological levels of EPO have substantial metabolic effects
UCP1 expression and respiration rates. The gene expression
(90). In the latter model study, EPO mimiced a myokine in
pattern of beige cells is distinct from either white or brown
that it is produced and secreted from skeletal muscles and ex-
fat. Beige cells are, however, preferentially sensitive to the
hibits paracrine and endocrine effects on other muscles. The
polypeptide hormone irisin, which turns beige cells into so-
DNA electrotransfer method represents, however, an artificial
called brite cells (252).
model to overexpress and secrete EPO from muscles and our
Peroxisome-proliferator-activated receptor-gamma
findings do not prove that EPO is indeed secreted natively
coactivator-1 alpha (PGC-1α) plays a critical role in the
from muscles. Of interest, however, Rundqvist et al. reported
maintenance of glucose, lipid, and energy homeostasis and
that EPO is released from the exercising leg to the circula-
is involved in the pathology associated with obesity-related
tion, possibly corresponding to an increased bioavailability
disorders such as diabetes, CVD and neurodegeneration
of EPO. This finding suggests that EPO may represent a true
(120). Moreover, muscle specific PGC-1α overexpression
myokine (207).
renders mice resistant to age-related obesity and diabetes and
increases lifespan (247) suggesting that PGC-1α may con-
tribute to regulate metabolism of other tissues, notably WAT. Conclusion
By comparing muscle gene-expression profiles of trans- EPO may represent a true myokine with various metabolic
genic and wild-type mice, it was recently demonstrated that effects on muscle and adipose tissue.
PGC-1α induced the expression of several genes with secreted
protein products, including FNDC5 (21). Irisin is a proteolytic
cleavage product of the membrane protein FNDC5 and its ex- Other myokines
pression within skeletal muscle was found to be increased by By building the so-called “Myo-mouse” that is able to in-
exercise in both mice and humans. Irisin is regulated by exer- duce growth of functional type II muscle by stimulating Akt-
cise. Thus, a twofold increase in basal plasma levels of irisin 1signaling, Kenneth Walsh, Boston has identified a couple of
was observed after 10 weeks of regular exercise in humans, muscle-secreted factors (98, 244). Follistatin-like 1 (FSTL-1)
suggesting that the FNDC5/irisin complex plays a role in is a myokine that activates Akt-Endothelial nitric oxide syn-
training adaptation to exercise. When mice were injected with thase (eNOS) signaling in endothelial cells and appears to
FNDC5 expressing adenoviral particles, the systemic levels of have cardioprotective effects (156, 159) (219).
irisin increased by three- to fourfold. Overexpression of irisin Overexpression of FSTL-1 stimulates ischemia-induced
induced a brown-fat cell-like development of WAT and con- revascularization in mice through activation of eNOS (159).

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Skeletal
muscle
Exercise PGC-1α

FNDC5

Irisin

White Brite

UCP1

Figure 8 Exercise increases the intramuscular expression of peroxisome prolif-

erator activated receptor γ coactivator 1α (PGC-1α). Boström and colleagues re-
cently reported that PGC-1α, a transcriptional coactivator, stimulates the expres-
sion of the membrane protein fibronectin type III domain containing 5 (FNDC5),
which is proteolytically cleaved to form irisin, a myokine. Irisin drives the transfor-
mation of white fat cells into brite cells—white fat cells with a phenotype similar
to that of brown fat cells, as indicated by a marked increase in the expression
of uncoupling protein 1 (UCP1) in white adipose tissue. The investigators also
showed that an elevated level of plasma irisin, achieved through gene replace-
ment, is followed by a reduction in body weight and an improvement in metabolic
homeostasis in obese mice. Adapted, with permission, from (168).

FGF21 induces hepatic expression of PGC-1α, which is
a key transcriptional regulator of energy homeostasis. More-
over, FGF21 causes corresponding increases in fatty acid ox-
idation, tricarboxylic acid cycle flux, and gluconeogenesis
without increasing glycogenesis (46, 194). Studies in humans
support that FGF-21 may be an insulin-regulated myokine
(92).
Insulin-like 6 (Insl6) was identified as a myokine that is
upregulated in skeletal muscle downstream of Akt signaling
and in regenerating muscle in response to injury. Skeletal
muscle-specific Insl6 transgenic mice exhibited normal mus-
cle mass under basal conditions but elevated satellite cell
activation and enhanced muscle regeneration in response to
injury. In addition, overexpression of Insl6-stimulated pro-
liferation and reduced apoptosis in cultured myogenic cells,
whereas knockdown of Insl6 reduced proliferation and in-
creased apoptosis. These data indicate that Insl6 is an injury-
regulated myokine that functions as a myogenic regenerative
factor. Interleukin-4 (IL-4) is a complex glycoprotein pro-
duced mostly by mast cells, basophils, a subset of activated T
cells, eosinophils, and neutrophils (35). Horsley et al. showed
that myogenic cells could be a target for IL-4 (94). They
demonstrated in a mouse model that IL-4 is a crucial factor
in muscle growth.
Lafreniere et al. (113) showed that IL-4 was secreted dur-
ing human myoblast differentiation and is required for my-
otube maturation. In addition, more recent studies suggest the
existence of secreted factors from muscle cells, which may
influence cancer cell growth (91) and distant organs such as
pancreas (22).
A role for myokines in muscle-bone interactions has been
suggested (76). Two well-known osteogenic factors, IGF-1
and FGF-2, are localized to the muscle-bone interface in vivo,
they are abundant in homogenized muscle tissue, and they are
secreted from cultured myotubes in vitro (172).
Myokine screening
As many as 10% of encoded human genes appear to have the
capacity to express proteins that potentially can be secreted

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from cells (244). A couple of research groups have con-
tributed to the identification of the muscle cell secretome
using various forms of proteomic analyses. In a study led by
Kratchmarowa, a quantitative proteomics platform was used
to investigate the factors secreted during the differentiation
of murine C2C12 skeletal muscle cells. This study identified
and quantitatively analyzed 635 secreted proteins, including
35 growth factors, 40 cytokines, and 36 metallopeptidases
(82). Yoon et al. treated differentiated L6 rat skeletal mus-
cle cells with or without insulin and comparatively analyzed
the proteins secreted into the media. They identified a total
of 254 proteins, among which 153 were classified as secre-
tory proteins. They reported that 14 proteins were secreted
at higher levels under insulin stimulation, including several
proteins known to be highly secreted in metabolic diseases
(254). A study led by Schiaffino and his group reported that
the resulting putative skeletal muscle secretome consisted of
319 proteins, including 78 still uncharacterized proteins (20).
Norheim and coinvestigators detected a total of 236 proteins
by proteome analysis in medium conditioned by cultured hu-
man myotubes. Interestingly, they also showed that 15 of the
secreted muscle proteins had markedly enhanced mRNA ex-
pression in the vastus lateralis and/or trapezius muscles after
11 weeks of strength training among healthy volunteers (153).
So far, the biological effects have been mapped for only some
of the identified myokines. However, it is obvious that several
myokines may serve as potential pharmaceutical targets and
provide a basis to explain the mechanisms whereby muscles
communicate with other organs.
Myokines in a Clinical Perspective
The identification of myokines provides a conceptual basis
for understanding how skeletal muscles communicate to other
organs and why several diseases occur in networks. According
to our theory, muscle disuse will lead to impaired myokine
production, which may cause simultaneous malfunction of
several organs and the occurrence of several diseases.
It is well known that many human diseases are dependent
on each other. They may occur in, for example, genetic
networks (13) or so-called social networks, which include all
human-to-human interactions (e.g., familial, friendship, sex-
ual, and proximity-based contacts) that play a role not only in
the spread of pathogens (13), but also in the spread of obesity.
It appears that friends have an even more important effect
on a person’s risk of obesity than genes do (36). The latter
study showed that if one friend became obese during a given
time interval, the other friend’s chances of following suit
increased by 171%. In contrast, if one sibling became obese,
the chance that the other would become obese increased
by 40%.
A couple of years ago, we suggested the existence of a
“lifestyle network” or more specifically a “physical inactivity
network” of key importance in understanding why several
diseases appear in clusters, although they are highly different
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Diseasome of physical inactivity
Type 2 diabetes
Cardiovascular
diseases
Breast cancer
Depression
Colon cancer
Dementia
Figure 9 Type 2 diabetes, cardiovascular diseases, colon cancer,
postmenopausal breast cancer, dementia, and depression constitute
a cluster of diseases, which can be identified as “the diseasome of
physical inactivity”. Adapted, with permission, from (165).
in terms of phenotypical presentation and required treatment
(165).
The diseasome of physical inactivity
The so-called “diseasome of physical inactivity” includes
type 2 diabetes, CVDs, colon cancer, postmenopausal breast
cancer, dementia, and depression, which constitute a cluster
of diseases (Fig. 9).
The above diagnoses are not meant to represent an exclu-
sive list of diseases or disorders related to physical inactiv-
ity. In fact, Booth et al. listed 35 chronic diseases in which
physical inactivity was thought to be a primary cause (19).
However, the diseases within the “diseasome of physical in-
activity” are all frequent chronic diseases, associated with an
enhanced risk of premature morbidity.
Physical inactivity increases the risk of type 2 diabetes
(238), CVDs (152), colon cancer (250), postmenopausal
breast cancer (137), dementia (204), and depression (161).
It has been documented that patients with type 2 diabetes
have a markedly increased risk of CVD (43). Furthermore,
type 2 diabetes is associated with both Alzheimer’s disease
and vascular dementia, and individuals with type 2 diabetes
also have a high prevalence of depression [reviewed in (111)].
In addition, it has been shown that patients with type 2 diabetes
have an elevated risk of cancer, for example, colon and breast
cancer (200). Thus, without doubt there is a major overlap
between several diagnoses within the diseasome of physical
inactivity, which points at the possibility that although these
disorders have very different phenotypical presentations, they
share some underlying pathogenetic mechanisms.
The identification of muscle as a secretory organ provides
the basis for a new understanding of how muscles communi-
cate with other organs such as adipose tissue, liver, pancreas,
bones, and brain. According to this new paradigm, exercise
leads to the production and release of a variety of myokines
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Physical inactivity

Abdominal adiposity

Macrophage infiltration of visceral fat

Chronic systemic inflammation

Insulin resistance, atherosclerosis, neurodegeneration, tumor growth

Diseasome of physical inactivity

Type 2 diabetes

Cardiovascular
Breast cancer diseases

Depression
Colon cancer

Dementia

Figure 10 Hypothesis: physical inactivity leads to accumulation of visceral fat and conse-
quently to the activation of a network of inflammatory pathways, which promotes develop-
ment of insulin resistance, atherosclerosis, neurodegeneration, and tumor growth, leading
to the development of “the diseasome of physical inactivity.” Adapted, with permission, from
(165).

that contribute to protect against a whole network of diseases,
including CVDs, type 2 diabetes, cancer, and cognitive
diseases.
The link between physical inactivity, abdominal
adiposity, and systemic inflammation
It is well supported that physical inactivity is an indepen-
dent and strong risk factor for accumulation of visceral fat
and consequently the activation of a network of inflamma-
tory pathways that promote development of insulin resis-
tance, atherosclerosis, neurodegenation, and tumor growth
and thereby also the development of the diseases belonging
to the “diseasome of physical inactivity” (165, 167) (Fig. 10).
Even a large amount of subcutaneous adipose tissue may
have only little or no damaging effect and may even offer
protection against chronic diseases, whereas strong evidence
exists for the detrimental effects of visceral fat and fat in the
liver and in muscle (165, 191).
Abdominal adiposity is associated with CVD (75), type 2
diabetes (16), dementia (248), colon cancer (65), and breast
cancer (253) as well as all-cause mortality independently
of body mass index, that is, also in people with a normal
body weight (191). Thus, it appears that the health conse-
quences of abdominal adiposity and physical inactivity are
very similar.
It is well known that both physical inactivity (175) and
abdominal adiposity (256) are associated with persistent sys-
temic low-grade inflammation (56, 77). Models of lipodys-
trophy suggest that if the subcutaneous fat becomes inflamed
and adipocytes undergo apoptosis/necrosis, the fat storing ca-
pacity is impaired and fat will consequently be deposited as
ectopic fat (34). One obvious explanation to the differential
outcome of accumulating fat subcutaneously or as ectopic
fat could be that when fat is stored in “the wrong places,” it
will stimulate an inflammatory response. Evidence exists that
visceral fat is more inflamed than subcutaneous fat and con-
stitutes an important source of systemic inflammation (256).
We recently conducted a real-life model of physical inac-
tivity that clearly demonstrated a direct link between physical
inactivity and accumulation of visceral fat. We included a
group of young healthy men, who did not train on a reg-
ular basis, and asked them to decrease their daily stepping
for 2 weeks to 1500 steps from the range recommended
for adults of around 10,000. During the 14 days of reduced
stepping, they developed a markedly impaired glucose toler-
ance as well as attenuation of postprandial lipid metabolism.
They experienced a 7% increase in intra-abdominal fat mass,

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Before
Figure 11 MR-scanning demonstrating visceral fat mass before and after 14 days of reduced daily
stepping as described in (155).
measured by Magnetic Resonance (MR)-scanning, without a
change in total fat mass while total fat-free mass and body
mass index decreased (155) (Fig. 11).
This was accompanied by a marked decline in periph-
eral insulin sensitivity without an effect on hepatic EGP. The
2-week period also induced a 7% decline in VO2 max
(mL/min; cardiovascular fitness).
Of note, 2 weeks of inactivity did not provoke an increase
in circulating levels of TNF. However, evidence exists of an
association between physical inactivity and low-grade sys-
temic inflammation in healthy, young individuals (187). These
findings are compatible with the notion that accumulation of
visceral fat actually precedes chronic systemic inflammation
and may represent the source of origin with regard to systemic
inflammation.
Although insulin resistance clearly can occur without
inflammation, it is constantly found that chronic low-grade
inflammation promotes or aggravates development of in-
sulin resistance, atherosclerosis, neurodegenation, and tumor
growth (77) and concomitantly the development of the dis-
eases belonging to the “diseasome of physical inactivity.”
Accumulating data suggest that although TNF-α is not the
pathogenetic factor, it plays a direct role in the metabolic syn-
drome [recently reviewed in (165,175)]. In short, patients with
diabetes have a high protein expression of TNF-α in skele-
tal muscle and increased TNF-α levels in plasma, and it is
likely that adipose tissue, which produces TNF-α, is the main
source of the circulating TNF-α. In vitro studies demonstrate
that TNF-α has direct inhibitory effects on insulin signaling.
In addition, TNF-α infusion in healthy humans induces in-
sulin resistance in skeletal muscle, without an effect on EGP.
It has also been proposed that TNF-α causes insulin resistance
indirectly in vivo by increasing the release of FFAs from adi-
pose tissue. TNF-α increases lipolysis in human and 3T3-L1
adipocytes. However, TNF-α has no effect on muscle fatty
acid oxidation, but increases fatty acid incorporation into di-
acylglycerol, which may be involved in the development of
the TNF-α-induced insulin resistance in skeletal muscle. In
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After
addition, evidence suggests that TNF-α plays a direct role
in linking insulin resistance to vascular disease (193, 257).
Moreover, in CVDs, activated immune cells also play ma-
jor roles, particularly in the etiology of atherosclerosis (127).
Importantly, also tumor initiation, promotion, and progres-
sion is stimulated by systemic elevation of proinflammatory
cytokines (77, 121).
Several downstream mediators and signaling pathways
seem to provide the cross talk between inflammatory and
metabolic signaling (165). These include the discovery of
JNK and I kappa beta kinase (IκβK) as critical regulators
of insulin action activated by TNF-α (96). In human TNF-
α infusion studies, TNF-α increases phosphorylation of p70
S6 kinase, extracellular signal-regulated kinase-1/2, and c-
Jun NH(2)-terminal kinase, concomitant with increased ser-
ine, and reduced tyrosine phosphorylation of insulin receptor
substrate-1. These signaling effects are associated with im-
paired phosphorylation of Akt substrate 160, the most proxi-
mal step identified in the insulin signaling cascade regulating
GLUT4 translocation and glucose uptake (193).
The role of IL-6 in insulin resistance is highly controver-
sial [as reviewed in (165, 175)]. In short, infusion of rhIL-6
into resting healthy humans has no effect on glucose home-
ostasis, although IL-6 contributes to the contraction-induced
increase in EGP.
A number of studies indicate that IL-6 enhances lipol-
ysis, as well as fat oxidation, via an activation of AMPK
[reviewed in (175)]. Consistent with this idea, Wallenius
et al. (243) demonstrated that IL-6-deficient mice developed
mature-onset obesity and insulin resistance. Of note, both
TNF-α and IL-6 induce lipolysis, whereas IL-6 only appears
to induce fat oxidation (192,241). Given the different biologi-
cal profiles of TNF-α and IL-6 and given that TNF-α may trig-
ger an IL-6 release, one theory holds that it is TNF-α derived
from adipose tissue that is actually the major “driver” behind
inflammation-induced insulin resistance and atherosclerosis.
The beneficial effect of exercise in the protection against
diseases associated with chronic inflammation may to some
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extent be ascribed to an anti-inflammatory effect of regu-
lar exercise. However, we have suggested that the long-term
anti-inflammatory effects of exercise may be mediated via
effects of exercise leading to a reduction in visceral fat mass
(165). IL-6 may also work in an endocrine fashion to increase
hepatic glucose production during exercise or lipolysis in adi-
pose tissue [reviewed in (175)]. However, although it has not
been demonstrated that IL-6 has specific effects on visceral fat
mass, it appears to play an important role in mediating AMPK-
induced fat oxidation in skeletal muscle. As described above,
IL-15 is a potential myokine, which appears to be involved
in the regulation of visceral fat as overexpression of IL-15
protected mice from obesity, especially with regard to accu-
mulation of visceral fat (141,143). In addition, BDNF appears
to work in an autocrine or paracrine fashion with strong ef-
fects on peripheral metabolism, including fat oxidation with a
subsequent effect on the size of adipose tissue (177). Finally,
EPO may play a role in muscle-fat cross-talk and contribute
to minimize the abdominal adiposity (90).
The anti-inflammatory effects of an acute bout
of exercise
Regular exercise appears to induce direct anti-inflammatory
effects, suggesting that physical activity per se may suppress
systemic low-grade inflammation (24, 68, 126, 144, 187, 188,
212).
A substantial amount of studies have demonstrated that
markers of inflammation are reduced following longer-term
behavioral changes involving both reduced energy intake and
increased physical activity [reviewed in (165, 187)].
A number of mechanisms may be responsible for this
effect. Exercise increases the release of epinephrine, cortisol,
growth hormone, prolactin, and other factors that have
immunomodulatory effects (77, 145, 165). Acute exercise
has been shown to induce a true anti-inflammatory response.
A model of “low grade inflammation” was established
in our laboratory. A very low dose of Escherichia. Coli
endotoxin was administered to healthy volunteers, who were
randomized to either rest or exercise prior to endotoxin
administration. In resting subjects, endotoxin induced a 2- to
threefold increase in circulating levels of TNF-α. In contrast,
when the subjects performed 3 h of ergometer cycling and
received the endotoxin bolus at 2.5 h, the TNF-α response
was totally blunted (224), suggesting that acute exercise may
inhibit TNF production.
The cytokine response to exercise differs markedly from
that elicited by severe infections in the fact that the clas-
sical proinflammatory cytokines, TNF-α and IL-1β, do not
increase with exercise [as reviewed in (175)].
In relation to exercise, IL-6 is the first cytokine released
into the blood. The level of circulating IL-6 increases in an
exponential fashion (up to 100-fold) during acute exercise and
declines in the postexercise period. The circulating levels of
the well-known anti-inflammatory cytokines, IL-1ra and IL-
10, also increase after exercise. Thus, exercise provokes an
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increase primarily in IL-6, followed by an increase in IL-1ra
and IL-10.
It has been clearly demonstrated that both the upstream
and downstream signaling pathways for IL-6 differ markedly
between myocytes and macrophages (Fig. 12).
Unlike IL-6 signaling in macrophages, which is dependent
upon activation of the NFκB signaling pathway, it appears
that intramuscular IL-6 expression is regulated by a network
of signaling cascades that among other pathways is likely
to involve cross-talk between the Ca2+/NFAT and glyco-
gen/p38 MAPK pathways. Therefore, when IL-6 is signaling
in monocytes or macrophages, it creates a proinflammatory
response, whereas IL-6 activation and signaling in muscle is
totally independent upon a preceding TNF-response or NFκB
activation (165, 175).
Without doubt, an acute bout of exercise elicits an anti-
inflammatory response and IL-6 appears to mediate some of
the anti-inflammatory effects of exercise (144, 187). IL-6 in-
hibits lipo polysaccharide (LPS)-induced TNF production in
cultured human monocytes (214). Other studies show that
levels of TNF-α are elevated in anti-IL-6-treated mice and in
IL-6 deficient knockout mice (135). In healthy humans, both
exercise and rhIL-6 infusion inhibit the endotoxin-induced
increase in circulating levels of TNF-α (224). Moreover, IL-6
contributes to mediate anti-inflammatory effects by stimulat-
ing the production of the classic anti-inflammatory cytokines
IL-1ra and IL-10 (229).
The possibility exists that with regular exercise, the anti-
inflammatory effects of an acute bout of exercise will protect
against chronic systemic low-grade inflammation, but such a
direct link between the acute effects of exercise and the long-
term benefits has yet to be established. Another possibility
is that regular exercise could protect against accumulation of
visceral fat and ectopic fat as such and thereby also protect
against chronic systemic inflammation.
The myokine concept provides a new platform for un-
derstanding some of the molecular mechanisms underlying
muscle organ, including muscle-fat cross-talk and for under-
standing the anti-inflammatory effects of exercise and thereby
how exercise may contribute to protect against a whole net-
work of chronic diseases with very different phenotypic
presentations.
Myokines in myogenesis
Although some myokines exert their actions on other organs
in a hormone-like fashion, many of them operate locally on
skeletal muscle itself. Skeletal muscles may adjust to increas-
ing demands by enlarging fiber size, and it is perhaps not
surprising that many of the factors secreted from the working
muscle act to regulate muscle hypertrophy and repair. In this
sense, myokines provide a feedback loop for the muscle to reg-
ulate its own growth and regeneration allowing, for example,
for adaptation to exercise training. Myokines may regulate
skeletal myogenesis in numerous ways, including a process
that involves sequential satellite cell activation and migration,
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Comprehensive Physiology Muscle as a Secretory Organ

Macrophage
LPS
CD14
Skeletal muscle

TLR4
MyD88 IRAKs

Ca2+
TRAF-6
Calcineurin
p38 MAPK
IKK-α IKK-β
IKK-γ
CREBP NFAT AP-1
p300 CBP
NF κ B

IL-1β IL-6
IL-6
TNF-α

Figure 12 The proposed cytokine signaling pathways for macrophages and contracting skeletal muscle. While it is well known that transcription
of interleukin-6 (IL-6) and other proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and IL-β is principally regulated by the
Toll like receptor (##TLR) receptor signaling cascade that results in nuclear translocation and activation of NFκB, evidence in contracting skeletal
muscle suggests that contraction leads to increased cytosolic Ca2+ and activation of p38 MAPK and/or calcineurin, which leads to activation of
transcription factors depending upon these upstream events. Adapted, with permission, from (175).

with subsequent proliferation and differentiation of myoblasts
into mature myotubes. In fact, each of these steps has been
shown to be regulated by one or more myokines.
In short, LIF increases myoblast proliferation and upreg-
ulates expression of c-Myc and Jun-b, while knockdown of
the LIF receptor leads to decreased myoblast proliferation,
suggesting a role for LIF as a positive regulator of satellite
cell proliferation (25).
IL-6 is expressed by human myoblasts (15, 41) and hu-
man cultured myotubes (104). Moreover, IL-6 is locally and
transiently produced by growing murine myofibers and asso-
ciated satellite cells (217). In addition, IL-6 is released from
human primary muscle cell cultures from healthy individuals
(72, 79) and from patients with type 2 diabetes (72).
IL-7 has been identified as a myokine secreted from differ-
entiating human myotubes (79). Although IL-7 expression has
been shown to increase throughout differentiation of cultured
muscle cells, the expression of the IL-7 receptor was shown to
be highest in undifferentiated cells. Haugen et al. showed that
the addition of recombinant IL-7 caused a decrease in mRNA
expression of both MYOG and MHC-2 and an upregulation
of the satellite cell marker Pax7, and furthermore increased
migration of satellite cells (79).
A central step of myocyte differentiation is the fusion of
myoblasts with existing fibers to form mature, multinucleated
myocytes. This process was demonstrated by Horsley et al.
to be regulated by IL-4 in mouse skeletal muscle. Muscle
cells lacking IL-4 have been shown to be smaller in size
and to have less myonuclei (95). Of note, IL-4 is secreted
from differentiating human muscle cell cultures and causes
increased migration but not proliferation of myoblasts (113).
Myostatin is a member of the TGF-β superfamily. In hu-
man skeletal myoblasts, myostatin negatively regulates pro-
liferation by an upregulation of the cyclin-dependent kinase
(Cdk) inhibitor p21, causing an inhibition of Cdk2 and the
Cdk2 downstream target retinoblastoma (129).
When we consider the numerous functions of myokines in
the regulation of skeletal muscle growth and maintenance, it
is possible that myokines may provide a potential therapeutic
target for the treatment of muscle growth and regeneration
disorders and explain why regular exercise retards aging pro-
cesses. By targeting these myogenic myokines, it might be
possible to ameliorate the symptoms of muscle wasting dis-
orders and age-related sarcopenia.
Conclusion
Final Conclusion
Two millennia ago, Hippocrates observed that “walking is
man’s best medicine.” Already then, the benefits of physical

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Physical activity
Myokines
Muscle hypertrophy (myostatin, LIF, IL-4, IL-6, IL-7, IL-15)
Adipose tissue oxidation (IL-6, BDNF)
Insulin sensitivity (IL-6)
Osteogenesis (IGF-1, FGF-2)
Anti-inflammation (IL-6)
Antitumor defence [unidentified secreted factor(s)]
Pancreas function [unidentified secreted factor(s)]
Decreased risk of chronic diseases and premature mortality
Figure 13 The finding that muscle produces and releases myokines
provides a conceptual basis for understanding some of the molecular
mechanisms that link physical activity to protection against premature
mortality (172).
activity to health were recognized. Since then, the benefits of
physical activity in lowering the risk of death from any cause
and improving longevity have been well documented (160). In
the past few years, exercise research has contributed tremen-
dously to our understanding of the benefits of exercise on a
molecular level and recently also to the concept of considering
skeletal muscle as a secretory organ. The identification of the
muscle secretome provides a new platform for understanding
how muscles communicate with other organs and to explain
how a healthy muscle tissue is developed and maintained
(Fig. 13). Some myokines may be involved in communicat-
ing to other organs, such as adipose tissue, liver, pancreas,
bones, and brain. However, some myokines exert their effects
within the muscle itself. Thus, myostatin, LIF, IL-4, IL-6, and
IL-7 are involved in muscle hypertrophy and myogenesis,
whereas BDNF and IL-6 are involved in AMPK-mediated fat
oxidation. BDNF and Insl6 are involved in regeneration fol-
lowing injury. IL-6 also appears to have systemic effects on
the liver, adipose tissue, and the immune system, and mediates
cross-talk between the intestine and pancreatic islets. Other
myokines include the osteogenic factors IGF-1 and FGF-2;
FSTL-1, which improve the endothelial function of the vascu-
lar system; and the PGC-1α-dependent myokine irisin, which
drives brown-fat-like development. Furthermore, studies in
the past few years suggest the existence of yet unidentified
factors, secreted from muscle cells, which may influence can-
cer cell growth and pancreas function.
The identification of the muscle secretome could set a new
agenda for the scientific community. Future studies should
1356
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Comprehensive Physiology
reveal how myokine production are regulated on the basal
level; whether myokine resistance and abnormal myokine sig-
naling are dominant in pathophysiology, whether myokines .
Myokines may be proven to play a role as biomarkers of phys-
ical activity/inactivity. They may also be useful in monitoring
exercise effects both with regard to disease and performance.
Considering the numerous functions of myokines in
the regulation of skeletal muscle growth and maintenance,
myokines provide a potential therapeutic target for the treat-
ment of muscle growth and regeneration disorders. Targeting
these myogenic myokines could thus provide means to ame-
liorate the symptoms of muscle wasting disorders, muscular
dystrophies, and age-related sarcopenia. It is possible that
physical inactivity or muscle disuse may lead to an altered or
impaired myokine response and/or resistance to the effects of
myokines, explaining why lack of physical activity increases
the risk of a whole network of diseases, such as cancer, CVDs,
type 2 diabetes, dementia, and osteoporosis.
Acknowledgements
I wish to gratefully acknowledge my collaborators, postdoc-
toral fellows, students, and technicians who have contributed
much of the work reported in this review. I want to thank
Inge Holm for critical review of the article. The Centre of
Inflammation and Metabolism (CIM) is supported by a grant
from the Danish National Research Foundation (02-512-55).
This study was further supported by the Danish Council for
Independent Research—Medical Sciences, the Commission
of the European Communities (Grant Agreement no. 223576-
MYOAGE). CIM is part of the UNIK Project: Food, Fitness
& Pharma for Health and Disease, supported by the Danish
Ministry of Science, Technology, and Innovation. CIM is a
member of DD2—the Danish Center for Strategic Research in
Type 2 Diabetes (the Danish Council for Strategic Research,
grant nos. 09-067009 and 09-075724). The Copenhagen Mus-
cle Research Centre is supported by a grant from the Capital
Region of Denmark.
References
1. Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, Xue YY,
Buechi L, Walz A, Richmond A, Strieter RM. The CXC chemokine
receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-
induced angiogenic activity. J Immunol 165: 5269-5277, 2000.
2. Allen DL, Cleary AS, Speaker KJ, Lindsay SF, Uyenishi J, Reed JM,
Madden MC, Mehan RS. Myostatin, activin receptor IIb, and follistatin-
like-3 gene expression are altered in adipose tissue and skeletal muscle
of obese mice. Am J Physiol Endocrinol Metab 294: E918-E927, 2008.
3. Allen DL, Hittel DS, McPherron AC. Expression and function of myo-
statin in obesity, diabetes, and exercise adaptation. Med Sci Sports Exerc
43: 1828-1835, 2011.
4. Alter J, Rozentzweig D, Bengal E. Inhibition of myoblast differentiation
by tumor necrosis factor alpha is mediated by c-Jun N-terminal kinase
1 and leukemia inhibitory factor. J Biol Chem 283: 23224-23234, 2008.
5. Alvarez B, Carbo N, Lopez-Soriano J, Drivdahl RH, Busquets S, Lopez-
Soriano FJ, Argiles JM, Quinn LS. Effects of interleukin-15 (IL-15) on
adipose tissue mass in rodent obesity models: Evidence for direct IL-15
action on adipose tissue. Biochim Biophys Acta 1570: 33-37, 2002.
Volume 3, July 2013
P1: OTA/XYZ P2: ABC
JWBT335-c120033 JWBT335/Comprehensive Physiology June 8, 2013 8:4
Comprehensive Physiology
6. Argiles JM, Lopez-Soriano J, Almendro V, Busquets S, Lopez-Soriano
FJ. Cross-talk between skeletal muscle and adipose tissue: A link with
obesity? Med Res Rev 25: 49-65, 2005.
7. Asmussen E. Ventilation at transition from rest to exercise. Acta Physiol
Scand 89: 68-78, 1973.
8. Astrom MB, Feigh M, Pedersen BK. Persistent low-grade inflammation
and regular exercise. Front Biosci (Schol Ed) 2: 96-105, 2010.
9. Austin L, Burgess AW. Stimulation of myoblast proliferation in culture
by leukaemia inhibitory factor and other cytokines. J Neurol Sci 101:
193-197, 1991.
10. Baggiolini M. Chemokines in pathology and medicine. J Intern Med
250: 91-104, 2001.
11. Bamberger AM, Jenatschke S, Schulte HM, Ellebrecht I, Beil FU,
Bamberger CM. Regulation of the human leukemia inhibitory factor
gene by ETS transcription factors. Neuroimmunomodulation 11: 10-
19, 2004.
12. Banzet S, Koulmann N, Simler N, Birot O, Sanchez H, Chapot R,
Peinnequin A, Bigard X. Fibre-type specificity of interleukin-6 gene
transcription during muscle contraction in rat: Association with cal-
cineurin activity. J Physiol 566: 839-847, 2005.
13. Barabasi AL. Network medicine–from obesity to the “diseasome”. N
Engl J Med 357: 404-407, 2007.
14. Barra NG, Reid S, MacKenzie R, Werstuck G, Trigatti BL, Richards C,
Holloway AC, Ashkar AA. Interleukin-15 contributes to the regulation
of murine adipose tissue and human adipocytes. Obesity (Silver Spring)
18: 1601-1607, 2010.
15. Bartoccioni E, Michaelis D, Hohlfeld R. Constitutive and cytokine-
induced production of interleukin-6 by human myoblasts. Immunol
Lett 42: 135-138, 1994.
16. Bays HE. “ Sick fat,” metabolic disease, and atherosclerosis. Am J Med
122: S26-S37, 2009.
17. Belperio JA, Keane MP, Arenberg DA, Addison CL, Ehlert JE, Burdick
MD, Strieter RM. CXC chemokines in angiogenesis. J Leukoc Biol 68:
1-8, 2000.
18. Bergfors M, Barnekow-Bergkvist M, Kalezic N, Lyskov E, Eriksson
JW. Short-term effects of repetitive arm work and dynamic exercise on
glucose metabolism and insulin sensitivity. Acta Physiol Scand 183:
345-356, 2005.
19. Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of
chronic diseases. Comprehensive Physiology, 2(2): 1143-1211, 2012.
20. Bortoluzzi S, Scannapieco P, Cestaro A, Danieli GA, Schiaffino S.
Computational reconstruction of the human skeletal muscle secretome.
Proteins 62: 776-792, 2006.
21. Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach
KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind
BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM. A PGC1-
alpha-dependent myokine that drives brown-fat-like development of
white fat and thermogenesis. Nature 481: 463-468, 2012.
22. Bouzakri K, Plomgaard P, Berney T, Donath MY, Pedersen BK, Halban
PA. Bimodal effect on pancreatic â-cells of secretory products from
normal or insulin-resistant human skeletal muscle. Diabetes 60: 1111-
1121, 2011.
23. Brandt C, Nielsen AR, Fischer CP, Hansen J, Pedersen BK, Plomgaard
P. Plasma and muscle myostatin in relation to type 2 diabetes. PLoS
One 7: e37236, 2012.
24. Brandt C, Pedersen BK. The role of exercise-induced myokines in
muscle homeostasis and the defense against chronic diseases. J Biomed
Biotechnol 2010: 520258, 2010.
25. Broholm C, Laye MJ, Brandt C, Vadalasetty R, Pilegaard H, Peder-
sen BK, Scheele C. LIF is a contraction-induced myokine stimulating
human myocyte proliferation. J Appl Physiol 111: 251-259, 2011.
26. Broholm C, Mortensen OH, Nielsen S, Akerstrom T, Zankari A, Dahl
B, Pedersen BK. Exercise induces expression of leukaemia inhibitory
factor in human skeletal muscle. J Physiol 586: 2195-2201, 2008.
27. Broholm C, Pedersen BK. Leukaemia inhibitory factor–an exercise-
induced myokine. Exerc Immunol Rev 16: 77-85, 2010.
28. Bruce CR, Dyck DJ. Cytokine regulation of skeletal muscle fatty acid
metabolism: Effect of interleukin-6 and tumor necrosis factor-alpha.
Am J Physiol Endocrinol Metab 287: E616-E621, 2004.
29. Bruunsgaard H, Galbo H, Halkjaer-Kristensen J, Johansen TL,
MacLean DA, Pedersen BK. Exercise-induced increase in interleukin-6
is related to muscle damage. J Physiol Lond 499: 833-841, 1997.
30. Carbo N, Lopez-Soriano J, Costelli P, Alvarez B, Busquets S, Bac-
cino FM, Quinn LS, Lopez-Soriano FJ, Argiles JM. Interleukin-15
mediates reciprocal regulation of adipose and muscle mass: A poten-
tial role in body weight control. Biochim Biophys Acta 1526: 17-24,
2001.
31. Carbo N, Lopez-Soriano J, Costelli P, Busquets S, Alvarez B, Baccino
FM, Quinn LS, Lopez-Soriano FJ, Argiles JM. Interleukin-15 antag-
onizes muscle protein waste in tumour-bearing rats. Br J Cancer 83:
526-531, 2000.
32. Carey AL, Febbraio MA. Interleukin-6 and insulin sensitivity: Friend
or foe? Diabetologia 47: 1135-1142, 2004.
Volume 3, July 2013
Printer Name: Yet to Come
Muscle as a Secretory Organ
33. Carey AL, Steinberg GR, Macaulay SL, Thomas WG, Holmes AG,
Ramm G, Prelovsek O, Hohnen-Behrens C, Watt MJ, James DE,
Kemp BE, Pedersen BK, Febbraio MA. Interleukin-6 increases insulin-
stimulated glucose disposal in humans and glucose uptake and fatty
acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55:
2688-2697, 2006.
34. Caron-Debarle M, Lagathu C, Boccara F, Vigouroux C, Capeau J. HIV-
associated lipodystrophy: From fat injury to premature aging. Trends
Mol Med 16: 218-229, 2010.
35. Chomarat P, Banchereau J. An update on interleukin-4 and its receptor.
Eur Cytokine Netw 8: 333-344, 1997.
36. Christakis NA, Fowler JH. The spread of obesity in a large social
network over 32 years. N Engl J Med 357: 370-379, 2007.
37. Christiansen T, Paulsen SK, Bruun JM, Pedersen SB, Richelsen B. Ex-
ercise training versus diet-induced weight-loss on metabolic risk factors
and inflammatory markers in obese subjects: A 12-week randomized
intervention study. Am J Physiol Endocrinol Metab 298: E824-E831,
2010.
38. Cook KS, Min HY, Johnson D, Chaplinsky RJ, Flier JS, Hunt CR,
Spiegelman BM. Adipsin: A circulating serine protease homolog se-
creted by adipose tissue and sciatic nerve. Science 237: 402-405, 1987.
39. Copray S, Liem R, Brouwer N, Greenhaff P, Habens F, Fernyhough
P. Contraction-induced muscle fiber damage is increased in soleus
muscle of streptozotocin-diabetic rats and is associated with elevated
expression of brain-derived neurotrophic factor mRNA in muscle fibers
and activated satellite cells. Exp Neurol 161: 597-608, 2000.
40. Crofford LJ. The hypothalamic-pituitary-adrenal axis in the pathogen-
esis of rheumatic diseases. Endocrinol Metab Clin North Am 31: 1-13,
2002.
41. De Rossi M, Bernasconi P, Baggi F, de Waal MR, Mantegazza R.
Cytokines and chemokines are both expressed by human myoblasts:
Possible relevance for the immune pathogenesis of muscle inflamma-
tion. Int Immunol 12: 1329-1335, 2000.
42. Dhawan J, Rando TA. Stem cells in postnatal myogenesis: Molecular
mechanisms of satellite cell quiescence, activation and replenishment.
Trends Cell Biol 15: 666-673, 2005.
43. Diamant M, Tushuizen ME. The metabolic syndrome and endothelial
dysfunction: Common highway to type 2 diabetes and CVD. Curr Diab
Rep 6: 279-286, 2006.
44. Diao Y, Wang X, Wu Z. SOCS1, SOCS3, and PIAS1 promote myogenic
differentiation by inhibiting the leukemia inhibitory factor-induced
JAK1/STAT1/STAT3 pathway. Mol Cell Biol 29: 5084-5093, 2009.
45. Dinarello CA, Mier JW. Interleukins. Annu Rev Med 37: 173-178, 1986.
46. Domouzoglou EM, Maratos-Flier E. Fibroblast growth factor 21 is a
metabolic regulator that plays a role in the adaptation to ketosis. Am J
Clin Nutr 93: 901S-905, 2011.
47. Ellingsgaard H, Ehses JA, Hammar EB, Van LL, Quintens R, Martens
G, Kerr-Conte J, Pattou F, Berney T, Pipeleers D, Halban PA, Schuit
FC, Donath MY. Interleukin-6 regulates pancreatic alpha-cell mass
expansion. Proc Natl Acad Sci U S A 105: 13163-13168, 2008.
48. Ellingsgaard H, Hauselmann I, Schuler B, Eppler E, Meier D, Bouzakri
K, Wueest S, Muller Y, Reinecke M, Konrad D, Gassmann M, Halban P,
Gromada J, Ehses J, Donath M. Interleukin-6 enhances insulin secretion
by increasing glucagon-like peptide-1 secretion from L cells and alpha
cells. Nat Med 17: 1481-1489, 2011.
49. Febbraio MA. Signaling pathways for IL-6 within skeletal muscle.
Exerc Immunol Rev 9: 34-9, 2003.
50. Febbraio MA, Hiscock N, Sacchetti M, Fischer CP, Pedersen BK.
Interleukin-6 is a novel factor mediating glucose homeostasis during
skeletal muscle contraction. Diabetes 53: 1643-1648, 2004.
51. Febbraio MA, Ott P, Nielsen HB, Steensberg A, Keller C, Krustrup P,
Secher NH, Pedersen BK. Hepatosplanchnic clearance of interleukin-
6 in humans during exercise. Am J Physiol Endocrinol Metab 285:
E397-E402, 2003.
52. Febbraio MA, Pedersen BK. Muscle-derived interleukin-6: Mecha-
nisms for activation and possible biological roles. FASEB J 16: 1335-
1347, 2002.
53. Febbraio MA, Pedersen BK. Contraction-induced myokine production
and release: Is skeletal muscle an endocrine organ? Exerc Sport Sci Rev
33: 114-119, 2005.
54. Febbraio MA, Steensberg A, Keller C, Starkie RL, Krustrup P, Ott P,
Secher NH, Pedersen BK. Glucose ingestion attenuates interleukin-6
release from contracting skeletal muscle in humans. J Physiol (London)
549: 607-612, 2003.
55. Feldman BJ, Streeper RS, Farese RV, Jr., Yamamoto KR. Myo-
statin modulates adipogenesis to generate adipocytes with favorable
metabolic effects. Proc Natl Acad Sci U S A 103: 15675-15680, 2006.
56. Festa A, D’Agostino R, Jr., Tracy RP, Haffner SM. Elevated levels of
acute-phase proteins and plasminogen activator inhibitor-1 predict the
development of type 2 diabetes: The insulin resistance atherosclerosis
study. Diabetes 51: 1131-1137, 2002.
57. Figueras M, Busquets S, Carbo N, Barreiro E, Almendro V, Argiles
JM, Lopez-Soriano FJ. Interleukin-15 is able to suppress the increased
1357
P1: OTA/XYZ P2: ABC
JWBT335-c120033 JWBT335/Comprehensive Physiology June 8, 2013 8:4
Muscle as a Secretory Organ
DNA fragmentation associated with muscle wasting in tumour-bearing
rats. FEBS Lett 569: 201-206, 2004.
58. Fischer CP. Interleukin-6 in acute exercise and training: What is the
biological relevance? Exerc Immunol Rev 12: 6-33, 2006.
59. Fischer CP, Hiscock N, Basu S, Vessby B, Kallner A, Sjöberg LB,
Febbraio MA, Pedersen BK. Supplementation with vitamins C and E
inhibits the release of interleukin-6 from contracting human skeletal
muscle. J Physiol 558: 633-645, 2004.
60. Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Saltin B, Pedersen
BK. Endurance training reduces the contraction-induced interleukin-6
mRNA expression in human skeletal muscle. Am J Physiol Endocrinol
Metab 287: E1189-E1194, 2004.
61. Furmanczyk PS, Quinn LS. Interleukin-15 increases myosin accretion
in human skeletal myogenic cultures. Cell Biol Int 27: 845-851, 2003.
62. Fuster G, Almendro V, Fontes-Oliveira CC, Toledo M, Costelli P,
Busquets S, Lopez-Soriano FJ, Argiles JM. Interleukin-15 affects dif-
ferentiation and apoptosis in adipocytes: Implications in obesity. Lipids
46: 1033-1042, 2011.
63. Gala RR. Prolactin and growth hormone in the regulation of the immune
system. Proc Soc Exp Biol Med 198: 513-527, 1991.
64. Giese B, Roderburg C, Sommerauer M, Wortmann SB, Metz S, Hein-
rich PC, Muller-Newen G. Dimerization of the cytokine receptors
gp130 and LIFR analysed in single cells. J Cell Sci 118: 5129-5140,
2005.
65. Giovannucci E. Metabolic syndrome, hyperinsulinemia, and colon can-
cer: A review. Am J Clin Nutr 86: s836-s842, 2007.
66. Gleeson M. Interleukins and exercise. J Physiol 529: 1, 2000.
67. Gleeson M. Immune function in sport and exercise. J Appl Physiol 103:
693-699, 2007.
68. Gleeson M, Bishop NC, Stensel DJ, Lindley MR, Mastana SS, Nimmo
MA. The anti-inflammatory effects of exercise: Mechanisms and impli-
cations for the prevention and treatment of disease. Nat Rev Immunol
11: 607-615, 2011.
69. Goldstein MS. Humoral nature of the hypoglycemic factor of muscular
work. Diabetes 10: 232-234, 1961.
70. Gomez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary
exercise induces a BDNF-mediated mechanism that promotes neuro-
plasticity. J Neurophysiol 88: 2187-2195, 2002.
71. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung
V, Beers C, Richardson J, Schoenborn MA, Ahdieh M. Cloning of a T
cell growth factor that interacts with the beta chain of the interleukin-2
receptor. Science 264: 965-968, 1994.
72. Green CJ, Pedersen M, Pedersen BK, Scheele C. Elevated NF-
{kappa}B activation is conserved in human myocytes cultured from
obese type 2 diabetic patients and attenuated by AMP-activated protein
kinase. Diabetes 60: 2810-2819, 2011.
73. Gregorevic P, Williams DA, Lynch GS. Effects of leukemia inhibitory
factor on rat skeletal muscles are modulated by clenbuterol. Muscle
Nerve 25: 194-201, 2002.
74. Guo T, Jou W, Chanturiya T, Portas J, Gavrilova O, McPherron AC.
Myostatin inhibition in muscle, but not adipose tissue, decreases fat
mass and improves insulin sensitivity. PLoS One 4: e4937, 2009.
75. Haffner SM. Abdominal adiposity and cardiometabolic risk: Do we
have all the answers? Am J Med 120: S10-S16, 2007.
76. Hamrick MW. A role for myokines in muscle-bone interactions. Exerc
Sport Sci Rev 39: 43-47, 2011.
77. Handschin C, Spiegelman BM. The role of exercise and PGC1[alpha]
in inflammation and chronic disease. Nature 454: 463-469, 2008.
78. Hansen J, Brandt C, Nielsen AR, Hojman P, Whitham M, Febbraio
MA, Pedersen BK, Plomgaard P. Exercise induces a marked increase
in plasma follistatin: Evidence that follistatin is a contraction-induced
hepatokine. Endocrinology 152: 164-171, 2011.
79. Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland S, Berg O, Fun-
derud A, Skalhegg BS, Raastad T, Drevon CA. IL-7 is expressed and
secreted by human skeletal muscle cells. Am J Physiol Cell Physiol
298: C807-C816, 2010.
80. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L.
Interleukin-6-type cytokine signalling through the gp130/Jak/STAT
pathway. Biochem J 334: 297-314, 1998.
81. Hellsten Y, Frandsen U, Orthenblad N, Sjodin N, Richter EA. Xanthine
oxidase in human skeletal muscle following eccentric exercise: A role
of inflammation. J Physiol (London) 498: 239-248, 1997.
82. Henningsen J, Rigbolt KT, Blagoev B, Pedersen BK, Kratchmarova I.
Dynamics of the skeletal muscle secretome during myoblast differen-
tiation. Mol Cell Proteomics 9: 2482-96, 2010.
83. Henson DA, Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Shan-
non M, Bolton MR, Davis JM, Gaffney CT, Kelln WJ, Austin MD,
Hjertman JM, Schilling BK. Influence of carbohydrate on cytokine
and phagocytic responses to 2 h of rowing. Med Sci Sports Exerc 32:
1384-1389, 2000.
84. Hilton DJ, Nicola NA, Metcalf D. Purification of a murine leukemia
inhibitory factor from Krebs ascites cells. Anal Biochem 173: 359-367,
1988.
1358
Printer Name: Yet to Come
Comprehensive Physiology
85. Hinds MG, Maurer T, Zhang JG, Nicola NA, Norton RS. Resonance
assignments, secondary structure and topology of leukaemia inhibitory
factor in solution. J Biomol NMR 9: 113-126, 1997.
86. Hirose L, Nosaka K, Newton M, Laveder A, Kano M, Peake J, Suzuki
K. Changes in inflammatory mediators following eccentric exercise of
the elbow flexors. Exerc Immunol Rev 10: 75-90.: 75-90, 2004.
87. Hiscock N, Chan MH, Bisucci T, Darby IA, Febbraio MA. Skeletal
myocytes are a source of interleukin-6 mRNA expression and protein
release during contraction: Evidence of fiber type specificity. FASEB J
18: 992-994, 2004.
88. Hittel DS, Berggren JR, Shearer J, Boyle K, Houmard JA. Increased
secretion and expression of myostatin in skeletal muscle from extremely
obese women. Diabetes 58: 30-38, 2009.
89. Hoene M, Weigert C. The role of interleukin-6 in insulin resistance,
body fat distribution and energy balance. Obes Rev 9: 20-29, 2008.
90. Hojman P, Brolin C, Gissel H, Brandt C, Zerahn B, Pedersen BK, Gehl
J. Erythropoietin over-expression protects against diet-induced obesity
in mice through increased fat oxidation in muscles. PLoS One 4: e5894,
2009.
91. Hojman P, Dethlefsen C, Brandt C, Hansen J, Pedersen L, Pedersen BK.
Exercise-induced muscle-derived cytokines inhibit mammary cancer
cell growth. Am J Physiol Endocrinol Metab 301: E504-E510, 2011.
92. Hojman P, Pedersen M, Nielsen AR, Krogh-Madsen R, Yfanti C, Ak-
erstrom T, Nielsen S, Pedersen BK. Fibroblast growth factor-21 is
induced in human skeletal muscles by hyperinsulinemia. Diabetes 58:
2797-2801, 2009.
93. Holmes AG, Watt MJ, Carey AL, Febbraio MA. Ionomycin, but
not physiologic doses of epinephrine, stimulates skeletal muscle
interleukin-6 mRNA expression and protein release. Metabolism 53:
1492-1495, 2004.
94. Horsley V, Jansen KM, Mills ST, Pavlath GK. IL-4 acts as a myoblast
recruitment factor during mammalian muscle growth. Cell 113: 483-
494, 2003.
95. Horsley V, Pavlath GK. Forming a multinucleated cell: Molecules that
regulate myoblast fusion. Cells Tissues Organs 176: 67-78, 2004.
96. Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes
Relat Metab Disord 27(Suppl 3): S53-S55, 2003.
97. Huang EJ, Reichardt LF. Neurotrophins: Roles in neuronal develop-
ment and function. Annu Rev Neurosci 24: 677-736, 2001.
98. Izumiya Y, Hopkins T, Morris C, Sato K, Zeng L, Viereck J, Hamilton
JA, Ouchi N, LeBrasseur NK, Walsh K. Fast/Glycolytic muscle fiber
growth reduces fat mass and improves metabolic parameters in obese
mice. Cell Metab 7: 159-172, 2008.
99. Johnson HM, Smith EM, Torres BA, Blalock JE. Regulation of the in
vitro antibody response by neuroendocrine hormones. Proc Natl Acad
Sci U S A 79: 4171-4174, 1982.
100. Jonsdottir IH, Schjerling P, Ostrowski K, Asp S, Richter EA, Pedersen
BK. Muscle contractions induce interleukin-6 mRNA production in rat
skeletal muscles. J Physiol (London) 528: 157-163, 2000.
101. Kahn BB, Alquier T, Carling D, Hardie DG. AMP-activated protein
kinase: Ancient energy gauge provides clues to modern understanding
of metabolism. Cell Metab 1: 15-25, 2005.
102. Kami K, Senba E. Localization of leukemia inhibitory factor and
interleukin-6 messenger ribonucleic acids in regenerating rat skeletal
muscle. Muscle Nerve 21: 819-822, 1998.
103. Keane MP, Arenberg DA, Lynch JP, III, Whyte RI, Iannettoni MD, Bur-
dick MD, Wilke CA, Morris SB, Glass MC, DiGiovine B, Kunkel SL,
Strieter RM. The CXC chemokines, IL-8 and IP-10, regulate angiogenic
activity in idiopathic pulmonary fibrosis. J Immunol 159: 1437-1443,
1997.
104. Keller C, Hellsten Y, Steensberg A, Pedersen BK. Differential regula-
tion of IL-6 and TNF-alpha via calcineurin in human skeletal muscle
cells. Cytokine 36: 141-147, 2006.
105. Keller C, Steensberg A, Hansen AK, Fischer CP, Plomgaard P, Pedersen
BK. The effect of exercise, training, and glycogen availability on IL-
6 receptor expression in human skeletal muscle. J Appl Physiol 99:
2075-2079, 2005.
106. Keller C, Steensberg A, Pilegaard H, Osada T, Saltin B, Pedersen BK,
Neufer PD. Transcriptional activation of the IL-6 gene in human con-
tracting skeletal muscle: Influence of muscle glycogen content. FASEB
J 15: 2748-2750, 2001.
107. Kelly M, Gauthier MS, Saha AK, Ruderman NB. Activation of AMP-
activated protein kinase (AMPK) by Interleukin-6 in rat skeletal muscle:
Association with changes in cAMP, energy state, and endogenous fuel
mobilization. Diabetes 58: 1953-1960, 2009.
108. Kim GY, Lee JW, Ryu HC, Wei JD, Seong CM, Kim JH. Proinflam-
matory cytokine IL-1beta stimulates IL-8 synthesis in mast cells via a
leukotriene B4 receptor 2-linked pathway, contributing to angiogenesis.
J Immunol 184: 3946-3954, 2010.
109. Kishimoto T. Signal transduction through homo- or heterodimers of
gp130. Stem Cells Dayt 12(Suppl 1): 37-44, 1994.
110. Kjaer M, Secher NH, Bangsbo J, Perko G, Horn A, Mohr T, Galbo
H. Hormonal and metabolic responses to electrically induced cycling
Volume 3, July 2013
P1: OTA/XYZ P2: ABC
JWBT335-c120033 JWBT335/Comprehensive Physiology June 8, 2013 8:4
Comprehensive Physiology
during epidural anesthesia in humans. J Appl Physiol 80: 2156-2162,
1996.
111. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka TA,
Kivipelto M, Hassinen M, Rauramaa TH, Pedersen BK, Rauramaa R.
BDNF is a novel marker of cognitive function in ageing women: The
DR’s EXTRA Study. Neurobiol Learn Mem 90: 596-603, 2008.
112. Kurek JB, Bower J, Romanella M, Austin L. Leukaemia inhibitory
factor treatment stimulates muscle regeneration in the mdx mouse.
Neurosci Lett 212: 167-170, 1996.
113. Lafreniere JF, Mills P, Bouchentouf M, Tremblay JP. Interleukin-4
improves the migration of human myogenic precursor cells in vitro and
in vivo. Exp Cell Res 312: 1127-1141, 2006.
114. Lancaster GI, Jentjens RL, Moseley L, Jeukendrup AE, Gleeson M.
Effect of pre-exercise carbohydrate ingestion on plasma cytokine, stress
hormone, and neutrophil degranulation responses to continuous, high-
intensity exercise. Int J Sport Nutr Exerc Metab 13: 436-453, 2003.
115. Li A, Dubey S, Varney ML, Dave BJ, Singh RK. IL-8 directly enhanced
endothelial cell survival, proliferation, and matrix metalloproteinases
production and regulated angiogenesis. J Immunol 170: 3369-3376,
2003.
116. Li TL, Gleeson M. The effect of single and repeated bouts of prolonged
cycling on leukocyte redistribution, neutrophil degranulation, IL-6, and
plasma stress hormone responses. Int J Sport Nutr Exerc Metab 14:
501-516, 2004.
117. Li TL, Gleeson M. The effects of carbohydrate supplementation dur-
ing the second of two prolonged cycling bouts on immunoendocrine
responses. Eur J Appl Physiol 95: 391-399, 2005.
118. Li TL, Wu CL, Gleeson M, Williams C. The effects of pre-exercise
high carbohydrate meals with different glycemic indices on blood
leukocyte redistribution, IL-6, and hormonal responses during a subse-
quent prolonged exercise. Int J Sport Nutr Exerc Metab 14: 647-656,
2004.
119. Lin J, Arnold HB, la-Fera MA, Azain MJ, Hartzell DL, Baile CA.
Myostatin knockout in mice increases myogenesis and decreases adi-
pogenesis. Biochem Biophys Res Commun 291: 701-706, 2002.
120. Lin J, Handschin C, Spiegelman BM. Metabolic control through the
PGC-1 family of transcription coactivators. Cell Metabolism 1: 361-
370, 2005.
121. Lin WW, Karin M. A cytokine-mediated link between innate immunity,
inflammation, and cancer. J Clin Invest 117: 1175-1183, 2007.
122. Lira SA, Zalamea P, Heinrich JN, Fuentes ME, Carrasco D, Lewin
AC, Barton DS, Durham S, Bravo R. Expression of the chemokine
N51/KC in the thymus and epidermis of transgenic mice results in
marked infiltration of a single class of inflammatory cells. J Exp Med
180: 2039-2048, 1994.
123. Lyngso D, Simonsen L, Bulow J. Interleukin-6 production in human
subcutaneous abdominal adipose tissue: The effect of exercise. J Phys-
iol 543: 373-378, 2002.
124. Ma Q. Beneficial effects of moderate voluntary physical exercise and
its biological mechanisms on brain health. Neurosci Bull 24: 265-270,
2008.
125. MacIntyre DL, Sorichter S, Mair J, Berg A, McKenzie DC. Markers of
inflammation and myofibrillar proteins following eccentric exercise in
humans. Eur J Appl Physiol 84: 180-186, 2001.
126. Mathur N, Pedersen BK. Exercise as a mean to control low-grade
systemic inflammation. Mediators Inflamm 2008: 109502, 2008.
127. Matter CM, Handschin C. RANTES (regulated on activation, normal T
cell expressed and secreted), inflammation, obesity, and the metabolic
syndrome. Circulation 115: 946-948, 2007.
128. Matthews VB, Astrom MB, Chan MH, Bruce CR, Krabbe KS,
Prelovsek O, Akerstrom T, Yfanti C, Broholm C, Mortensen OH,
Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Ped-
ersen BK, Febbraio MA. Brain-derived neurotrophic factor is produced
by skeletal muscle cells in response to contraction and enhances fat
oxidation via activation of AMP-activated protein kinase. Diabetologia
52: 1409-1418, 2009.
129. McFarlane C, Hui GZ, Amanda WZ, Lau HY, Lokireddy S, Xiaojia
G, Mouly V, Butler-Browne G, Gluckman PD, Sharma M, Kambadur
R. Human myostatin negatively regulates human myoblast growth and
differentiation. Am J Physiol Cell Physiol 301: C195-C203, 2011.
130. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle
mass in mice by a new TGF-beta superfamily member. Nature 387:
83-90, 1997.
131. McPherron AC, Lee SJ. Suppression of body fat accumulation in
myostatin-deficient mice. J Clin Invest 109: 595-601, 2002.
132. Metcalf D. The unsolved enigmas of leukemia inhibitory factor. Stem
Cells 21: 5-14, 2003.
133. Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D,
Kahn BB. Leptin stimulates fatty-acid oxidation by activating AMP-
activated protein kinase. Nature 415: 339-343, 2002.
134. Miura P, Amirouche A, Clow C, Belanger G, Jasmin BJ. Brain-derived
neurotrophic factor expression is repressed during myogenic differen-
tiation by miR-206. J Neurochem 120: 230-238, 2012.
Volume 3, July 2013
Printer Name: Yet to Come
Muscle as a Secretory Organ
135. Mizuhara H, O’Neill E, Seki N, Ogawa T, Kusunoki C, Otsuka K,
Satoh S, Niwa M, Senoh H, Fujiwara H. T cell activation-associated
hepatic injury: Mediation by tumor necrosis factors and protection by
interleukin 6. J Exp Med 179: 1529-1537, 1994.
136. Mohr T, Andersen JL, Biering-Sorensen F, Galbo H, Bangsbo J, Wag-
ner A, Kjaer M. Long-term adaptation to electrically induced cycle
training in severe spinal cord injured individuals. Spinal Cord 35: 1-16,
1997.
137. Monninkhof EM, Elias SG, Vlems FA, van dT, I, Schuit AJ, Voskuil
DW, van Leeuwen FE. Physical activity and breast cancer: A systematic
review. Epidemiology 18: 137-157, 2007.
138. Mousavi K, Jasmin BJ. BDNF is expressed in skeletal muscle satellite
cells and inhibits myogenic differentiation. J Neurosci 26: 5739-5749,
2006.
139. Mucci P, Durand F, Lebel B, Bousquet J, Prefaut C. Interleukins 1-beta,
-8, and histamine increases in highly trained, exercising athletes. Med
Sci Sports Exerc 32: 1094-1100, 2000.
140. Nehlsen Cannarella SL, Fagoaga OR, Nieman DC, Henson DA, But-
terworth DE, Schmitt RL, Bailey EM, Warren BJ, Utter A, Davis JM.
Carbohydrate and the cytokine response to 2.5 h of running. J Appl
Physiol 82: 1662-1667, 1997.
141. Nielsen AR, Hojman P, Erikstrup C, Fischer CP, Plomgaard P, Mounier
R, Mortensen OH, Broholm C, Taudorf S, Krogh-Madsen R, Linde-
gaard B, Petersen AM, Gehl J, Pedersen BK. Association between
IL-15 and obesity: IL-15 as a potential regulator of fat mass. J Clin
Endocrinol Metab 93: 4486-93, 2008.
142. Nielsen AR, Mounier R, Plomgaard P, Mortensen OH, Penkowa M,
Speerschneider T, Pilegaard H, Pedersen BK. Expression of interleukin-
15 in human skeletal muscle effect of exercise and muscle fibre type
composition. J Physiol 584: 305-312, 2007.
143. Nielsen AR, Pedersen BK. The biological roles of exercise-induced
cytokines: IL-6, IL-8, and IL-15. Appl Physiol Nutr Metab 32: 833-
839, 2007.
144. Nielsen S, Pedersen BK. Skeletal muscle as an immunogenic organ.
Curr Opin Pharmacol 8: 346-351, 2008.
145. Nieman DC. Current perspective on exercise immunology. Curr Sports
Med Rep 2: 239-242, 2003.
146. Nieman DC, Davis JM, Brown VA, Henson DA, Dumke CL, Utter AC,
Vinci DM, Downs MF, Smith JC, Carson J, Brown A, McAnulty SR,
McAnulty LS. Influence of carbohydrate ingestion on immune changes
after 2 h of intensive resistance training. J Appl Physiol 96: 1292-1298,
2004.
147. Nieman DC, Davis JM, Henson DA, Gross SJ, Dumke CL, Ut-
ter AC, Vinci DM, Carson JA, Brown A, McAnulty SR, McAnulty
LS, Triplett NT. Muscle cytokine mRNA changes after 2.5 h of cy-
cling: Influence of carbohydrate. Med Sci Sports Exerc 37: 1283-1290,
2005.
148. Nieman DC, Davis JM, Henson DA, Walberg-Rankin J, Shute M,
Dumke CL, Utter AC, Vinci DM, Carson JA, Brown A, Lee WJ, McAn-
ulty SR, McAnulty LS. Carbohydrate ingestion influences skeletal mus-
cle cytokine mRNA and plasma cytokine levels after a 3-h run. J Appl
Physiol 94: 1917-1925, 2003.
149. Nieman DC, Henson DA, McAnulty SR, McAnulty L, Swick NS, Utter
AC, Vinci DM, Opiela SJ, Morrow JD. Influence of vitamin C supple-
mentation on oxidative and immune changes after an ultramarathon.
J Appl Physiol 92: 1970-1977, 2002.
150. Nieman DC, Henson DA, Smith LL, Utter AC, Vinci DM, Davis JM,
Kaminsky DE, Shute M. Cytokine changes after a marathon race.
J Appl Physiol 91: 109-114, 2001.
151. Nieman DC, Nehlsen-Canarella SL, Fagoaga OR, Henson DA, Utter
A, Davis JM, Williams F, Butterworth DE. Influence of mode and
carbohydrate on the cytokine response to heavy exertion. Med Sci Sports
Exerc 30: 671-678, 1998.
152. Nocon M, Hiemann T, Muller-Riemenschneider F, Thalau F, Roll S,
Willich SN. Association of physical activity with all-cause and car-
diovascular mortality: A systematic review and meta-analysis. Eur J
Cardiovasc Prev Rehabil 15: 239-246, 2008.
153. Norheim F, Raastad T, Thiede B, Rustan AC, Drevon CA, Haugen
F. Proteomic identification of secreted proteins from human skeletal
muscle cells and expression in response to strength training. Am J
Physiol Endocrinol Metab 301: E1013-E1021, 2011.
154. Nosaka K, Clarkson PM. Changes in indicators of inflammation after
eccentric exercise of the elbow flexors. Med Sci Sports Exerc 28: 953-
961, 1996.
155. Olsen RH, Krogh-Madsen R, Thomsen C, Booth FW, Pedersen BK.
Metabolic responses to reduced daily steps in healthy nonexercising
men. JAMA 299: 1261-1263, 2008.
156. Oshima Y, Ouchi N, Sato K, Izumiya Y, Pimentel DR, Walsh K.
Follistatin-like 1 is an Akt-regulated cardioprotective factor that is se-
creted by the heart. Circulation 117: 3099-3108, 2008.
157. Ostrowski K, Hermann C, Bangash A, Schjerling P, Nielsen JN, Ped-
ersen BK. A trauma-like elevation of plasma cytokines in humans in
response to treadmill running. J Physiol 513: 889-894, 1998.
1359
P1: OTA/XYZ P2: ABC
JWBT335-c120033 JWBT335/Comprehensive Physiology June 8, 2013 8:4
Muscle as a Secretory Organ
158. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Chemokines
are elevated in plasma after strenuous exercise in humans. Eur J Appl
Physiol 84: 244-245, 2001.
159. Ouchi N, Oshima Y, Ohashi K, Higuchi A, Ikegami C, Izumiya Y,
Walsh K. Follistatin-like 1, a secreted muscle protein, promotes en-
dothelial cell function and revascularization in ischemic tissue through
a nitric-oxide synthase-dependent mechanism. J Biol Chem 283: 32802-
32811, 2008.
160. Paffenbarger RS, Jr., Hyde RT, Wing AL, Hsieh CC. Physical activity,
all-cause mortality, and longevity of college alumni. N Engl J Med 314:
605-613, 1986.
161. Paffenbarger RS, Jr., Lee IM, Leung R. Physical activity and personal
characteristics associated with depression and suicide in American col-
lege men. Acta Psychiatr Scand Suppl 377: 16-22, 1994.
162. Pedersen BK. Special feature for the Olympics: Effects of exercise on
the immune system: Exercise and cytokines. Immunol Cell Biol 78:
532-535, 2000.
163. Pedersen BK. The anti-inflammatory effect of exercise: Its role in dia-
betes and cardiovascular disease control. Essays Biochem 42: 105-117,
2006.
164. Pedersen BK. IL-6 signalling in exercise and disease. Biochem Soc
Trans 35: 1295-1297, 2007.
165. Pedersen BK. The diseasome of physical inactivity and the role
of myokines in muscle-fat cross talk. J Physiol 587: 5559-5568,
2009.
166. Pedersen BK. Exercise-induced myokines and their role in chronic
diseases. Brain Behav Immun 25: 811-816, 2011.
167. Pedersen BK. Muscles and their myokines. J Exp Biol 214: 337-346,
2011.
168. Pedersen BK. A muscular twist on the fate of fat. N Engl J Med 366:
1544-1545, 2012.
169. Pedersen BK. Muscular IL-6 and Its Role as an Energy Sensor. Med
Sci Sports Exerc 44: 392-396, 2012.
170. Pedersen BK, Akerstrom TC, Nielsen AR, Fischer CP. Role of
myokines in exercise and metabolism. J Appl Physiol 103(3): 1093-
1090, 2007.
171. Pedersen BK, Febbraio M. Muscle-derived interleukin-6: A possible
link between skeletal muscle, adipose tissue, liver, and brain. Brain
Behav Immun 19: 371-376, 2005.
172. Pedersen BK, Febbraio MA. Muscle, exercise and obesity: Skeletal
muscle as a secretory organ. Nature Reviews Endocrinology 3: 457-
465, 2012.
173. Pedersen BK, Fischer CP. Beneficial health effects of exercise—the
role of IL-6 as a myokine. Trends Pharmacol Sci 28: 152-156,
2007.
174. Pedersen BK, Fischer CP. Physiological roles of muscle-derived
interleukin-6 in response to exercise. Curr Opin Clin Nutr Metab Care
10: 265-271, 2007.
175. Pedersen BK, Febbraio MA. Muscle as an endocrine organ: Fo-
cus on muscle-derived interleukin-6. Physiol Rev 88: 1379-1406,
2008.
176. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system:
Regulation, integration and adaptation. Physiol Rev 80: 1055-1081,
2000.
177. Pedersen BK, Pedersen M, Krabbe KS, Bruunsgaard H, Matthews VB,
Febbraio MA. Role of exercise-induced brain-derived neurotrophic fac-
tor production in the regulation of energy homeostasis in mammals. Exp
Physiol 94: 1153-60, 2009.
178. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard
P, Febbraio M, Saltin B. Searching for the exercise factor: Is IL-6 a
candidate? J Muscle Res Cell Motil 24: 113-119, 2003.
179. Pedersen BK, Steensberg A, Fischer C, Keller C, Keller P, Plomgaard
P, Wolsk-Petersen E, Febbraio M. The metabolic role of IL-6 produced
during exercise: Is IL-6 an exercise factor? Proc Nutr Soc 63: 263-267,
2004.
180. Pedersen BK, Steensberg A, Keller P, Keller C, Fischer C, Hiscock
N, Hall Gv, Plomgaard P, Febbraio MA. Muscle-derived interleukin-6:
Lipolytic, anti-inflammatory and immune regulatory effects. Pflugers
Arch 446: 9-16, 2003.
181. Pedersen BK, Steensberg A, Schjerling P. Exercise and interleukin-6.
Curr Opin Hematol 8: 137-141, 2001.
182. Pedersen BK, Steensberg A, Schjerling P. Muscle-derived interleukin-
6: Possible biological effects. J Physiol (London) 536: 329-337,
2001.
183. Pedersen BK, Tvede N, Hansen FR, Andersen V, Bendix T, Bendixen
G, Bendtzen K, Galbo H, Haahr PM, Klarlund K and et al. Modulation
of natural killer cell activity in peripheral blood by physical exercise.
Scand J Immunol 27: 673-678, 1988.
184. Pedersen BK, Febbraio MA, Mooney RA. Interleukin-6 does/does not
have a beneficial role in insulin sensitivity and glucose homeostasis.
J Appl Physiol 102: 814-816, 2007.
185. Pedersen L, Pilegaard H, Hansen J, Brandt C, Adser H, Hidalgo J,
Olesen J, Pedersen BK, Hojman P. Exercise-induced liver CXCL-1
1360
Printer Name: Yet to Come
Comprehensive Physiology
expression is linked to muscle derived IL-6 expression. J Physiol 589:
1409-1420, 2011.
186. Pelletier M, Montplaisir S, Dardenne M, Bach JF. Thymic hormone
activity and spontaneous autoimmunity in dwarf mice and their litter-
mates. Immunology 30: 783-788, 1976.
187. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise.
J Appl Physiol 98: 1154-1162, 2005.
188. Petersen AM, Pedersen BK. The role of IL-6 in mediating the anti-
inflammatory effects of exercise. J Physiol Pharmacol 57(Suppl 10):
43-51, 2006.
189. Petersen EW, Carey AL, Sacchetti M., Steinberg GR, Macaulay SL,
Febbraio M.A., Pedersen BK. Acute IL-6 treatment increases fatty
acid turnover in elderly humans in vivo and in tissue culture in vitro:
Evidence that IL-6 acts independently of lipolytic hormones. Am J
Physiol 288: E155-E162, 2005.
190. Phillips SM, Green HJ, Tarnopolsky MA, Heigenhauser GF, Hill RE,
Grant SM. Effects of training duration on substrate turnover and oxi-
dation during exercise. J Appl Physiol 81: 2182-2191, 1996.
191. Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Over-
vad K, van der Schouw YT, Spencer E, Moons KGM, Tjonneland A,
Halkjaer J, Jensen MK, Stegger J, Clavel-Chapelon F, Boutron-Ruault
MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D,
Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PHM,
May AM, Bueno-De-Mesquita HB, van Duijnhoven FJB, Hallmans G,
Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barri-
carte A, Navarro C, Martinez C, Quiros JR, Key T, Bingham S, Khaw
KT, Boffetta P, Jenab M, Ferrari P, Riboli E. General and abdominal
adiposity and risk of death in Europe. New Engl J Med 359: 2105-2120,
2008.
192. Plomgaard P, Fischer CP, Ibfelt T, Pedersen BK, van HG. TNF-alpha
modulates human in vivo lipolysis. J Clin Endocrinol Metab 93: 543-9,
2007.
193. Plomgaard P, Keller P, Keller C, Pedersen BK. TNF-alpha, but not
IL-6, stimulates plasminogen activator inhibitor-1 expression in hu-
man subcutaneous adipose tissue. J Appl Physiol 98: 2019-2023,
2005.
194. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mo-
hammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC.
FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid
metabolism during the adaptive starvation response. Proc Natl Acad
Sci U S A 106: 10853-10858, 2009.
195. Quinn LS, Anderson BG. Interleukin-15, IL-15 receptor-alpha, and
obesity: Concordance of laboratory animal and human genetic studies.
J Obes 2011: 456347, 2011.
196. Quinn LS, Anderson BG, Drivdahl RH, Alvarez B, Argiles JM. Over-
expression of interleukin-15 induces skeletal muscle hypertrophy in
vitro: Implications for treatment of muscle wasting disorders. Exp Cell
Res 280: 55-63, 2002.
197. Quinn LS, Anderson BG, Strait-Bodey L, Stroud AM, Argiles JM.
Oversecretion of interleukin-15 from skeletal muscle reduces adiposity.
Am J Physiol Endocrinol Metab 296: E191-E202, 2009.
198. Quinn LS, Haugk KL, Damon SE. Interleukin-15 stimulates C2 skeletal
myoblast differentiation. Biochem Biophys Res Commun 239: 6-10,
1997.
199. Quinn LS, Strait-Bodey L, Anderson BG, Argiles JM, Havel PJ.
Interleukin-15 stimulates adiponectin secretion by 3T3-L1 adipocytes:
Evidence for a skeletal muscle-to-fat signaling pathway. Cell Biol Int
29: 449-457, 2005.
200. Richardson LC, Pollack LA. Therapy insight: Influence of type 2 dia-
betes on the development, treatment and outcomes of cancer. Nat Clin
Pract Oncol 2: 48-53, 2005.
201. Riechman SE, Balasekaran G, Roth SM, Ferrell RE. Association of
interleukin-15 protein and interleukin-15 receptor genetic variation
with resistance exercise training responses. J Appl Physiol 97: 2214-
2219, 2004.
202. Rodgers BD, Garikipati DK. Clinical, agricultural, and evolutionary
biology of myostatin: A comparative review. Endocr Rev 29: 513-534,
2008.
203. Rosendal L, Sogaard K, Kjaer M, Sjogaard G, Langberg H, Kristiansen
J. Increase in interstitial interleukin-6 of human skeletal muscle with
repetitive low-force exercise. J Appl Physiol 98: 477-481, 2005.
204. Rovio S, Kareholt I, Helkala EL, Viitanen M, Winblad B, Tuomilehto
J, Soininen H, Nissinen A, Kivipelto M. Leisure-time physical activity
at midlife and the risk of dementia and Alzheimer’s disease. Lancet
Neurol 4: 705-711, 2005.
205. Rubio N, Sanz-Rodriguez F. Induction of the CXCL1 (KC) chemokine
in mouse astrocytes by infection with the murine encephalomyelitis
virus of Theiler. Virology 358: 98-108, 2007.
206. Ruderman NB, Keller C, Richard AM, Saha AK, Luo Z, Xiang X,
Giralt M, Ritov VB, Menshikova EV, Kelley DE, Hidalgo J, Pedersen
BK, Kelly M. Interleukin-6 regulation of AMP-activated protein kinase:
Potential role in the systemic response to exercise and prevention of the
metabolic syndrome. Diabetes 55(Suppl 2): S48-S54, 2006.
Volume 3, July 2013
P1: OTA/XYZ P2: ABC
JWBT335-c120033 JWBT335/Comprehensive Physiology June 8, 2013 8:4
Comprehensive Physiology
207. Rundqvist H, Rullman E, Sundberg CJ, Fischer H, Eisleitner K,
Stahlberg M, Sundblad P, Jansson E, Gustafsson T. Activation of the
erythropoietin receptor in human skeletal muscle. Eur J Endocrinol
161: 427-434, 2009.
208. Sakuma K, Watanabe K, Sano M, Uramoto I, Totsuka T. Differential
adaptation of growth and differentiation factor 8/myostatin, fibroblast
growth factor 6 and leukemia inhibitory factor in overloaded, regener-
ating and denervated rat muscles. Biochim Biophys Acta 1497: 77-88,
2000.
209. Sakuma K, Watanabe K, Sano M, Uramoto I, Totsuka T. Postnatal
profiles of myogenic regulatory factors and the receptors of TGF-beta
2, LIF and IGF-I in the gastrocnemius and rectus femoris muscles of
dy mouse. Acta Neuropathol 99: 169-176, 2000.
210. Sakuma K, Yamaguchi A. The recent understanding of the neu-
rotrophin’s role in skeletal muscle adaptation. J Biomed Biotechnol
2011: 201696, 2011.
211. Scheele C, Nielsen S, Kelly M, Broholm C, Nielsen AR, Taudorf S,
Pedersen M, Fischer CP, Pedersen BK. Satellite cells derived from
obese humans with type 2 diabetes and differentiated into myocytes
in vitro exhibit abnormal response to IL-6. PLoS One 7: e39657,
2012.
212. Scheele C, Nielsen S, Pedersen BK. ROS and myokines promote
muscle adaptation to exercise. Trends Endocrinol Metab 20: 95-99,
2009.
213. Scherer PE. Adipose tissue: From lipid storage compartment to en-
docrine organ. Diabetes 55: 1537-1545, 2006.
214. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello
CA. Correlations and interactions in the production of interleukin-
6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood
mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75: 40-47,
1990.
215. Schmelzer CH, Burton LE, Tamony CM. Purification and partial char-
acterization of recombinant human differentiation-stimulating factor.
Protein Expr Purif 1: 54-62, 1990.
216. Seidl K, Erck C, Buchberger A. Evidence for the participation of nerve
growth factor and its low-affinity receptor (p75NTR) in the regulation
of the myogenic program. J Cell Physiol 176: 10-21, 1998.
217. Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M, Munoz-Canoves P.
Interleukin-6 is an essential regulator of satellite cell-mediated skeletal
muscle hypertrophy. Cell Metab 7: 33-44, 2008.
218. Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and dis-
ease: Evaluation of adiponectin-targeted drug development strategies.
Trends Pharmacol Sci 30: 234-239, 2009.
219. Shimano M, Ouchi N, Nakamura K, van WB, Ohashi K, Asaumi Y,
Higuchi A, Pimentel DR, Sam F, Murohara T, van den Hoff MJ, Walsh
K. Cardiac myocyte follistatin-like 1 functions to attenuate hypertrophy
following pressure overload. Proc Natl Acad Sci U S A 108: E899-E906,
2011.
220. Smith PE. Effect of hypophysectomy on the involution of the thymus
in the rat. Anat Rec 47: 119-129, 1930.
221. Spangelo BL, Gorospe WC. Role of the cytokines in the
neuroendocrine-immune system axis. Front Neuroendocrinol 16: 1-22,
1995.
222. Spangenburg EE, Booth FW. Multiple signaling pathways mediate LIF-
induced skeletal muscle satellite cell proliferation. Am J Physiol Cell
Physiol 283: C204-C211, 2002.
223. Spangenburg EE, Booth FW. Leukemia inhibitory factor restores the
hypertrophic response to increased loading in the LIF(-/-) mouse. Cy-
tokine 34: 125-130, 2006.
224. Starkie R, Ostrowski SR, Jauffred S, Febbraio M, Pedersen BK. Exer-
cise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production
in humans. FASEB J 17: 884-886, 2003.
225. Starkie RL, Angus DJ, Rolland J, Hargreaves M, Febbraio M. Effect of
prolonged submaximal exercise and carbohydrate ingestion on mono-
cyte intracellular cytokine production in humans. J Physiol (London)
528: 647-655, 2000.
226. Starkie RL, Arkinstall MJ, Koukoulas I, Hawley JA, Febbraio MA.
Carbohydrate ingestion attenuates the increase in plasma interleukin-6,
but not skeletal muscle interleukin-6 mRNA, during exercise in humans.
J Physiol (London) 533: 585-591, 2001.
227. Starkie RL, Rolland J, Angus DJ, Anderson MJ, Febbraio MA. Circu-
lating monocyes are not the source of elevations in plasma IL-6 and
TNF-alpha levels after prolonged running. Am J Physiol Cell Physiol
280: C769-C774, 2001.
228. Steensberg A, Febbraio MA, Osada T, Schjerling P, van HG, Saltin B,
Pedersen BK. Interleukin-6 production in contracting human skeletal
muscle is influenced by pre-exercise muscle glycogen content. J Physiol
537: 633-639, 2001.
229. Steensberg A, Fischer CP, Keller C, Moller K, Pedersen BK. IL-6
enhances plasma IL-1ra, IL-10, and cortisol in humans. Am J Physiol
Endocrinol Metab 285: E433-E437, 2003.
230. Steensberg A, Fischer CP, Sacchetti M, Keller C, Osada T, Schjerling
P, van Hall G, Febbraio MA, Pedersen BK. Acute interleukin-6 admin-
Volume 3, July 2013
Printer Name: Yet to Come
Muscle as a Secretory Organ
istration does not impair muscle glucose uptake or whole body glucose
disposal in healthy humans. J Physiol 548: 631-638, 2003.
231. Steensberg A, Keller C, Starkie RL, Osada T, Febbraio MA, Pedersen
BK. IL-6 and TNF-alpha expression in, and release from, contracting
human skeletal muscle. Am J Physiol Endocrinol Metab 283: E1272-
E1278, 2002.
232. Steensberg A, van HG, Osada T, Sacchetti M, Saltin B, Klarlund PB.
Production of interleukin-6 in contracting human skeletal muscles can
account for the exercise-induced increase in plasma interleukin-6. J
Physiol 529(Pt 1): 237-242, 2000.
233. Steinberg GR, Rush JW, Dyck DJ. AMPK expression and phosphory-
lation are increased in rodent muscle after chronic leptin treatment. Am
J Physiol Endocrinol Metab 284: E648-E654, 2003.
234. Steinberg GR, Watt MJ, Febbraio MA. Cytokine regulation of AMPK
signalling. Front Biosci 14: 1902-1916, 2009.
235. Sun L, Ma K, Wang H, Xiao F, Gao Y, Zhang W, Wang K, Gao X, Ip
N, Wu Z. JAK1-STAT1-STAT3, a key pathway promoting proliferation
and preventing premature differentiation of myoblasts. J Cell Biol 179:
129-138, 2007.
236. Suzuki K, Nakaji S, Yamada M, Liu Q, Kurakake S, Okamura N, Kumae
T, Umeda T, Sugawara K. Impact of a competitive marathon race on
systemic cytokine and neutrophil responses. Med Sci Sports Exerc 35:
348-355, 2003.
237. Tseng YL, Wu MH, Yang HC, Wang CY, Lin CF. Autocrine IL-6
regulates GRO-alpha production in thymic epithelial cells. Cytokine
51: 195-201, 2010.
238. Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Hamalainen H,
Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Louheranta
A, Rastas M, Salminen V, Uusitupa M. Prevention of type 2 diabetes
mellitus by changes in lifestyle among subjects with impaired glucose
tolerance. N Engl J Med 344: 1343-1350, 2001.
239. Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer Kristensen J,
Pedersen BK. Bicycle exercise enhances plasma IL-6 but does not
change IL-1alpha, IL-1beta, IL-6, or TNF-alpha pre-mRNA in BMNC.
J Appl Physiol 77: 93-7., 1994.
240. van der, V, Janssen TW. The potential anti-inflammatory effect of
exercise in chronic obstructive pulmonary disease. Respiration 79: 160-
174, 2010.
241. van Hall G, Steensberg A, Sacchetti M, Fischer C, Keller C, Schjer-
ling P, Hiscock N, Moller K, Saltin B, Febbraio MA, Pedersen BK.
Interleukin-6 stimulates lipolysis and fat oxidation in humans. J Clin
Endocrinol Metab 88: 3005-3010, 2003.
242. Wagers AJ, Conboy IM. Cellular and molecular signatures of muscle
regeneration: Current concepts and controversies in adult myogenesis.
Cell 122: 659-667, 2005.
243. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dick-
son SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop
mature-onset obesity. Nat Med 8: 75-79, 2002.
244. Walsh K. Adipokines, myokines and cardiovascular disease. Circ J 73:
13-18, 2009.
245. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA,
Bishop NC, Fleshner M, Green C, Pedersen BK, Hoffman-Goetz L,
Rogers CJ, Northoff H, Abbasi A, Simon P. Position statement. Part
one: Immune function and exercise. Exerc Immunol Rev 17: 6-63,
2011.
246. Watt MJ, Dzamko N, Thomas WG, Rose-John S, Ernst M, Carling
D, Kemp BE, Febbraio MA, Steinberg GR. CNTF reverses obesity-
induced insulin resistance by activating skeletal muscle AMPK. Nat
Med 12: 541-548, 2006.
247. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. In-
creased muscle PGC-1alpha expression protects from sarcopenia and
metabolic disease during aging. Proc Natl Acad Sci U S A 106: 20405-
20410, 2009.
248. Whitmer RA, Gustafson DR, Barrett-Connor E, Haan MN, Gunderson
EP, Yaffe K. Central obesity and increased risk of dementia more than
three decades later. Neurology 71: 1057-1064, 2008.
249. Willoughby DS, McFarlin B, Bois C. Interleukin-6 expression after
repeated bouts of eccentric exercise. Int J Sports Med 24: 15-21,
2003.
250. Wolin KY, Yan Y, Colditz GA, Lee IM. Physical activity and colon
cancer prevention: A meta-analysis. Br J Cancer 100: 611-616,
2009.
251. Wolsk E, Mygind H, Grondahl TS, Pedersen BK, van HG. IL-6 se-
lectively stimulates fat metabolism in human skeletal muscle. Am J
Physiol Endocrinol Metab 299: E832-E840, 2010.
252. Wu J, Bostrom P, Sparks LM, Ye L, Choi JH, Giang AH, Khandekar
M, Virtanen KA, Nuutila P, Schaart G, Huang K, Tu H, van Marken
Lichtenbelt WD, Hoeks J, Enerback S, Schrauwen P, Spiegelman BM.
Beige adipocytes are a distinct type of thermogenic fat cell in mouse
and human. Cell; 150: 366-376, 2012.
253. Xue F, Michels KB. Diabetes, metabolic syndrome, and breast can-
cer: A review of the current evidence. Am J Clin Nutr 86: s823-s835,
2007.
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Muscle as a Secretory Organ Comprehensive Physiology

254. Yoon JH, Yea K, Kim J, Choi YS, Park S, Lee H, Lee CS, Suh PG,
Ryu SH. Comparative proteomic analysis of the insulin-induced L6
myotube secretome. Proteomics 9: 51-60, 2009.
255. You T, Nicklas BJ. Effects of exercise on adipokines and the metabolic
syndrome. Curr Diab Rep 8: 7-11, 2008.
256. Yudkin JS. Inflammation, obesity, and the metabolic syndrome. Horm
Metab Res 39: 707-709, 2007.
257. Yudkin JS, Eringa E, Stehouwer CD. “ Vasocrine” signalling from
perivascular fat: A mechanism linking insulin resistance to vascular
disease. Lancet 365: 1817-1820, 2005.
258. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.
Positional cloning of the mouse obese gene and its human homologue.
Nature 372: 425-432, 1994.
259. Zhao B, Wall RJ, Yang J. Transgenic expression of myostatin propeptide
prevents diet-induced obesity and insulin resistance. Biochem Biophys
Res Commun 337: 248-255, 2005.

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