REVIEW ARTICLE

Interleukin-6 myokine signaling in skeletal muscle:

a double-edged sword?
~ oz-Ca
Pura Mun noves1, Camilla Scheele2, Bente K. Pedersen2 and Antonio L. Serrano1
 Catalana de Recerca i
1 Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), Institucio
Estudis Avancßats (ICREA), CIBER on Neurodegenerative diseases (CIBERNED), Barcelona, Spain
2 The Centre of Inflammation and Metabolism, Department of Infectious Diseases and CMRC, Rigshospitalet, University of Copenhagen,
Denmark

Keywords Interleukin (IL)-6 is a cytokine with pleiotropic functions in different tis-

growth/atrophy; IL-6; inflammation; sues and organs. Skeletal muscle produces and releases significant levels of
metabolism; myogenesis; myokine;
IL-6 after prolonged exercise and is therefore considered as a myokine.
regeneration; satellite cell; signaling
Muscle is also an important target of the cytokine. IL-6 signaling has been
pathway; skeletal muscle
associated with stimulation of hypertrophic muscle growth and myogenesis
Correspondence through regulation of the proliferative capacity of muscle stem cells. Addi-
P. Mun~oz-Canoves and A. L. Serrano, Cell tional beneficial effects of IL-6 include regulation of energy metabolism,
Biology Group, Department of Experimental which is related to the capacity of actively contracting muscle to synthesize
and Health Sciences, Pompeu Fabra and release IL-6. Paradoxically, deleterious actions for IL-6 have also been
University (UPF), 08003, Barcelona, Spain
proposed, such as promotion of atrophy and muscle wasting. We review
Fax: +34 93 316 0901
the current evidence for these apparently contradictory effects, the mecha-
Tel: +34 93 316 0891
E-mails: [email protected]; antonio. nisms involved and discuss their possible biological implications.
[email protected]

Note
Pura Mun~oz-Canoves and Antonio L.
Serrano contributed equally to this work

(Received 28 February 2013, revised 25

April 2013, accepted 7 May 2013)

doi:10.1111/febs.12338

Introduction
Adult skeletal muscle is a dynamic tissue capable of fibroblast growth factor, transforming growth factor b
responding to environmental stimuli in addition to being and interleukin (IL)-4. These factors have been shown
an organ that produces and secretes trophic factors. to control skeletal muscle homeostasis, regeneration and
Numerous cytokines and growth factors are produced growth, in part by regulating critical muscle stem cell
by the muscle itself, or by infiltrating inflammatory cells (satellite cell) functions. During the last decade, several
during regeneration. These cytokines include hepatocyte members of the IL-6 family, particularly IL-6 and leuke-
growth factor, insulin-like growth factor (IGF1), mia inhibitory factor (LIF), have also been recognized

Abbreviations
Ang II, angiotensin II; ERK, extracellular signal-regulated kinase; IGF, insulin-like growth factor; IGFBP3, IGF-binding protein-3; IL, interleukin;
IL-6R, IL-6 receptor; JAK, Janus kinase; LIF, leukemia inhibitory factor; MAPK, mitogen-activated protein kinase; PIAS, protein inhibitor of
activated STAT; SAA, serum amyloid A; SOCS, suppressor of cytokine signaling; STAT, signal transducer and activator of transcription;
TGFb, transforming growth factor b; TNF, tumor necrosis factor.

FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS 4131
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IL-6 myokine signaling in skeletal muscle ~oz-C
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as myokines, that is, cytokines produced by the working body-producing plasma cells, and induce T-cell growth
skeletal muscle during exercise [1–4]. and differentiation [5]. IL-6 may also act as a growth
factor for some cell types, although it appears to inhi-
bit the growth of others ([5]; see also below), in addi-
The IL-6 family of cytokines
tion to possessing many other effects. One of its most
IL-6 was first cloned and characterized in the mid- important roles is in fever because it not only crosses
1980s by several independent groups assessing immu- the blood–brain barrier to stimulate prostaglandin E2
noglobulin production and acute-phase protein synthesis in the hypothalamus, but it also facilitates
responses in different cell lines [5]. Although at first peripheral heat production by mediating the mobiliza-
characterized as interferon-b2, amongst other names, it tion of fuels for heat production in adipose tissue and
has since gone on to become the cytokine of reference of course skeletal muscle [9]. Indeed, although IL-6 is
for a subgroup of molecules. IL-6 belongs to the by definition pleiotropic, it is also one of the few genu-
broader four-a-helix family, in which members are ine myokines, or cytokines that are produced by and/
structurally defined by a 3D structure of four bundles or act on skeletal muscle. In response to muscle stress,
of a helices, and is the most studied of the IL-6 family satellite cells are activated, proliferate, differentiate
which also includes IL-11, IL-27, IL-31, ciliary neuro- and fuse to form new myofibers. The IL-6 family of
trophic factor, cardiotrophin-1, cardiotrophin-like cytokines released by either the muscle compartment
cytokine, LIF, neuropoietin and oncostatin M (myofibers and/or satellite cells) and/or by infiltrating
(reviewed in Ref. [6]). One of the defining features of inflammatory cells might potentially trigger and con-
this family is that they signal via the ubiquitously trol the distinct actions of satellite cells throughout the
expressed transmembrane protein gp130 (CD130). myogenic process.
Moreover, IL-6 signaling is further complicated by its
ability to operate via both ‘classical’ and ‘trans-signal-
Skeletal myogenesis
ing’ mechanisms.
In classical IL-6 signaling, the cytokine first binds to Formation of skeletal muscle (myogenesis) in the
the membrane-bound IL-6 receptor (IL-6R; CD126) mammalian embryo relies on muscle progenitor cells
that is induced to associate with a homodimer of gp130 which express Pax3 and Pax7, two paired-homeobox
which then transmits the intracellular signal. Expres- transcription factors responsible for myogenic lineage
sion of the IL-6R is limited to several cell types includ- specification. After birth, these progenitors adopt a
ing hepatocytes, neutrophils, monocytes/macrophages satellite position outside the myofiber and under the
and some lymphocytes [7] and thus the range of actions basal lamina, hence the name satellite cells. Sometime
of IL-6 is theoretically limited. However, alternative around postnatal day 21 they enter a quiescent state
splicing and limited proteolytic processing of IL-6R [10,11]. However, in response to external signals
generate a soluble and secreted form of the receptor derived from stress or trauma, quiescent satellite cells
(sIL-6R) that is found in many body fluids. Unlike are activated and undergo asymmetric division to both
many other soluble receptors, sIL-6R is not only able maintain the satellite cell pool through self-renewal
to bind to IL-6, but the IL-6–sIL-6 complex is able to and to generate a progeny of committed myoblasts
bind to and activate gp130 homodimers on cells that [12]. It is these myoblasts that subsequently proliferate,
do not express membrane-bound IL-6R, thereby medi- migrate, differentiate and fuse into new myofibers,
ating ‘trans-signaling’ and increasing the potential thereby maintaining adult muscle homeostasis and
range of IL-6 target tissues and activities [7]. IL-6 fam- repairing the injured muscle tissue (reviewed in Ref.
ily members typically signal through the common [11]).
gp130 receptor, with the Janus kinase/signal transducer Activation of a muscle-specific transcription factor
and activator of transcription (JAK/STAT) pathway network composed of four muscle-specific regulatory
being the major intracellular mediator of their effects. factors is fundamental for the formation of new myofi-
IL-6 is principally defined as a proinflammatory bers. These muscle-specific regulatory factors, Myf5,
cytokine (reviewed in Ref. [5]). For example, in IL-6- MyoD, myogenin and MRF4, all belong to the basic
deficient mice, the inflammatory acute-phase response helix–loop–helix family of transcription factors. They
after tissue damage or infection is severely compro- cooperate with ubiquitous E proteins (the E2A gene
mised [8]. In addition, IL-6-deficient mice also have products, E12 and E47, and HEB), and with MEF2
reduced IgG and IgA, but not IgM, responses, transcription factors on muscle gene promoters,
whereas T-cell activity is also blunted because IL-6 is thereby inducing expression of muscle-specific genes
able to induce the differentiation of B cells to anti- [13–16]. Recent studies have also demonstrated an epi-

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genetic level of regulation during myogenesis, blast proliferation, an effect that likely occurs via
involving both chromatin modifications and microR- induction of the cell proliferation-associated factors
NAs [17–19]. Thus, transition of satellite cells from a c-Myc and JunB. These effects can be abrogated by
quiescent (repressive) to an activated state in response genetic interference with the LIF receptor. Treatment
to environmental signals is caused by a combination of with IL-6 also promotes murine satellite cell prolifera-
genetic and epigenetic events, which in turn determine tion via regulation of the cell-cycle-associated genes
the gene expression program of the satellite cells at the cyclin D1 and c-myc [21]. Importantly, a complemen-
distinct myogenic stages. The IL-6 cytokine family, tary role to IL-6 in stimulating muscle growth may be
their downstream effectors and their actions in differ- attributed to IL-4 because it promotes myoblast fusion
ent models of skeletal muscle growth and repair are without affecting their proliferative capacity [23]. Simi-
the focus of this review. lar to IL-6, IL-4 is produced by exercising muscle
[4,24] and the expression of both cytokines has been
shown to depend on the transcription factor serum
Beneficial effects of IL-6 on muscle
response factor. Thus, serum response factor can be
formation and growth
used by the myofibers to translate mechanical cues
into paracrine growth-promoting signals that impact
Regulation of adult skeletal muscle growth and
positively on satellite cell proliferation and fusion [22].
regeneration by the IL-6 cytokine family
Functional studies in rodents have shown that IL-6
There are several approaches to studying the role of and LIF also contribute to muscle regeneration after
satellite cells and trophic factors in muscle function. injury and this may involve a similar stimulatory effect
Relatively simpler models such as denervation (atro- on satellite cell proliferation [25–28]. However, the cel-
phy) and overloading (compensatory hypertrophy), lular source of IL-6 and LIF in the damaged muscle
where the sciatic nerve is severed or where the soleus tissue is less clear than in overloaded muscle. It is
and plantaris muscles are forced to compensate for the likely that distinct cell types contribute to increasing
loss of the surgically isolated gastrocnemius, respec- the local production of cytokines, which in turn
tively, are two examples that occur in the absence of impact on satellite cells to modify their reparative
inflammation, thereby minimizing the confounding functions. In regenerating muscle, IL-6 is produced by
contribution of inflammatory cells. For example, infiltrating macrophages and neutrophils [28], by fibro-
increasing the mechanical load on adult skeletal muscle adipogenic progenitors [29], as well as by satellite cells
by overloading constitutes one of the most extreme [30,31], thus implying potential paracrine and auto-
modes of inducing hypertrophic growth of the tissue. crine functions of IL-6 in satellite cell-dependent myo-
IL-6 and LIF are induced in overloaded muscles dur- genesis. Early studies showed that cultured human
ing the process of hypertrophy in rodents [20–22]. LIF myoblasts produced and secreted IL-6 in response to
(and IL-6) expression is also significantly induced by treatment with proinflammatory cytokines such as
resistance exercise in human muscle and in electrically IL-1b or tumor necrosis factor (TNF)a [32]. Thus,
stimulated cultured human myotubes [3]. Confirming inflammatory cells infiltrating the injured muscle not
the role of these cytokines in muscle hypertrophy, both only produce IL-6, but also may secrete other
LIF and IL-6 knockout mice were shown to have an proinflammatory cytokines which might lead to fur-
impaired hypertrophic response to overloading [20,21]. ther IL-6 expression by satellite cells, thus increasing
Myofiber hypertrophy in response to overloading the concentration of IL-6 in the local satellite cell
requires not only increased net protein synthesis, but microenvironment.
also accretion of new nuclei from the progeny of satel- This local increase in IL-6 may lead not only to pro-
lite cells. Notably, the impaired hypertrophic muscle liferation of satellite cells, but also to their differentia-
growth in IL-6 null mice has been ascribed to blunted tion and fusion, thus playing a dual role in
accretion of myonuclei, while protein synthesis path- myogenesis. For example, cultured myoblasts undergo-
ways are preserved [21]. This impaired myonuclei ing differentiation have been shown to be a source of
incorporation is a consequence of the defective prolif- IL-6 and, more importantly, ablation of IL-6 expres-
eration and migration capacities of satellite cells in the sion with specific siRNAs reduced the extent of myo-
absence of IL-6 [21], reinforcing the idea that muscle- blast differentiation and fusion. However, genetic
produced IL-6 critically regulates satellite cell func- overexpression or addition of exogenous IL-6 aug-
tions. Similarly, LIF has been shown to control the mented the expression of muscle-specific genes, sup-
proliferation of satellite cells both in mice and humans porting its promyogenic function [33]. The requirement
[3]. Indeed, exogenous LIF can induce human myo- of IL-6 for myogenic differentiation has been recently

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confirmed genetically, because myoblasts derived from In recent years, much additional progress has been
IL-6 null mice displayed reduced differentiation and made in the understanding of the role of the JAK/
fusion capacities in vitro [34]. Like IL-6, LIF has also STAT pathway as an essential intracellular mediator
been associated with myoblast differentiation [35]. of the IL-6 family of cytokines in myogenesis, particu-
Thus, the IL-6 family of cytokines appears as a pivotal larly from studies by Wu and colleagues [48–51].
regulator of myogenesis, acting during both prolifera- In vivo analysis of JAK1, STAT1 and STAT3 mole-
tion and differentiation. This dual mode of action is cules in regenerating muscles has revealed that they
similar to IGF, a critical regulator of myogenesis, are activated at early times when satellite cells prolifer-
which can promote both proliferation and differentia- ate rapidly [48]. Consistent with this, the JAK1/
tion of satellite cells. Even more interestingly, it has STAT1/STAT3 pathway was shown to be necessary
been proposed that during myogenic differentiation, for myoblast proliferation in vitro, based on its capac-
IGF1 can activate the signal transducer and activator ity to regulate the expression of cell-cycle-associated
of transcription/suppressor of cytokine signaling genes such as p27, p21 and Id1. Further analysis
(STAT/SOCS) pathway [36], which has classically been showed that stimulation of myoblast proliferation by
associated with the intracellular transmission of IL-6 LIF treatment requires formation of a STAT1/STAT3
cytokine family signals. complex, because genetic interference with these mole-
cules abrogates LIF-mediated proliferation. This result
is consistent with the delayed muscle regeneration of
Activation of distinct JAK/STAT signaling
LIF / mice, which can be rescued by delivery of
pathways by the IL-6 family of cytokines regulate
exogenous LIF [25]. Thus, LIF is essential for the pro-
satellite cell-dependent myogenesis
liferation of myoblasts both in vivo and in vitro. Con-
Many intracellular signaling pathways are known to sistent with this, IL-6-dependent activation of STAT3
regulate myogenesis. Among them, the p38 mitogen- was also shown to be required for satellite cell prolifer-
activated protein kinase (MAPK), insulin-like growth ation in response to muscle overloading, and inhibition
factor/phosphatidylinositol 3-kinase/AKT, calcium/cal- of this pathway in IL-6 null mice impaired myofiber
modulin-activated protein kinase, and calcineurin posi- hypertrophy in vivo as well as satellite cell proliferation
tively regulate myogenic differentiation [16,37–40]. in vitro [21,22].
Alternatively, the extracellular signal-regulated kinase However, important studies by Wu and colleagues
(ERK) pathway has dual roles: it inhibits differentia- demonstrated that activation of the JAK1/STAT1/
tion at the early stage of differentiation, but promotes STAT3 pathway not only stimulates myoblast prolifer-
myocyte fusion at the late stages of differentiation [41– ation, but also prevents their premature differentiation
43]. Similarly, NF-KB has been shown to promote by blocking the expression of genes critical for myo-
myoblast proliferation, while also favoring differentia- blast differentiation and fusion, such as MyoD, MEF2
tion at later stages by acting as a downstream mediator and myogenin [48]. In this way, the JAK1/STAT1/
of p38 MAPK signaling [33,44]. Interestingly, IL-6 STAT3 pathway constitutes a differentiation check-
expression in differentiating myoblasts was shown to point, ensuring that differentiation commences only
depend on p38 MAPK and NF-KB signaling pathways, when a sufficient number of myoblast cell progeny
and is an effector of their myogenic activities [33]. have been generated during the proliferative phase.
Consistent with the dual functions of IL-6 and LIF Consistent with this, specific knockdown of JAK1 or
in myogenesis that have emerged in recent years, the STAT1 reduces myoblast proliferation and leads to
JAK/STAT signaling pathway has also been associated premature differentiation. Thus, LIF, and to certain
with both promotion of myoblast proliferation and/or extent, IL-6, play dual roles in proliferating myoblasts
differentiation. The distinct myogenic actions appear by inducing the JAK1/STAT1/STAT3 pathway, which
to depend on the particular intracellular mediators of is able to promote their proliferation and also inhibit
the JAK/STAT pathway engaged at every step. Early their precocious differentiation. Interestingly, exposure
studies showed that proliferating satellite cells in of myoblasts to LIF in differentiating conditions
regenerating muscle-expressed activated (phosphory- appeared to maintain the number of proliferating cells
lated) STAT3 [31], and cultured myoblasts showed as differentiation proceeded [52]. More precisely, LIF
expression of activated STAT3 when stimulated with treatment reduced the percentage of cells positive for
LIF [45,46]. In addition, STAT3 was shown to be active caspase 3 through a MEK/ERK-dependent
capable of associating directly with MyoD and inhibit- pathway. Because previous studies had shown that cas-
ing its myogenic activities when overexpressed in pase 3 activity is required for myogenic differentiation
C2C12 cells [47]. [53], LIF might inhibit differentiation not only via

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modulation of the JAK1/STAT1/STAT3 pathway, but principally targets activated STAT1 in the cell nucleus
also through inhibition of caspase 3. and prevents it from binding to DNA. The inhibition
At variance with the JAK1-mediated actions, Wu’s at distinct levels and positions might function to
group demonstrated that JAK2 is required for myo- ensure that the pathway can be effectively turned off
genic differentiation in a pathway requiring STAT2 thus allowing progression of myogenesis. The fact that
and STAT3, because pharmacological and genetic STAT1 and STAT3 are capable of inducing the inhibi-
interference with JAK2, STAT2 or STAT3 activation tion of the pathway by activating the expression of
prevented the differentiation process [49]. Whereas the SOCS1 and SOCS2, but not PIAS1, in a feedback
JAK1/STAT1/STAT3 pathway repressed the expres- inhibitory mechanism constitutes a further level of
sion of MyoD and MEF2, the JAK2/STAT2/STAT3 specificity and regulation of this pathway during myo-
pathway enhanced their expression, consistent with genesis [50]. It is worth noting that in differentiating
their opposite action on myogenesis. The JAK2/ myoblasts, IGF was shown to induce SOCS gene tran-
STAT2/STAT3 pathway also regulates the expression scription, suggesting that this protein could be
of hepatocyte growth factor and IGF2 in differentiat- involved in the differentiation process [36]. In agree-
ing cells [49]. The expression of hepatocyte growth fac- ment with this notion, SOCS3 overexpression in
tor was shown to be repressed by the JAK2/STAT2/ human myoblasts resulted in an increased expression
STAT3 pathway at the initial stages of differentiation of genes associated with skeletal muscle growth,
in agreement with the known role of this growth factor although the mechanism underlying this effect requires
in promoting proliferation and inhibiting differentia- further investigation [36]. Interestingly, SOCS3 signal-
tion. Alternatively, IGF2 was induced by the same ing during aging appears dysregulated [57,58], and
pathway as differentiation progressed, a result consis- therefore, the decline in the regenerative capacity of
tent with the capacity of IGF2 to stimulate myotube muscle with aging may be connected to STAT3/SOCS3
formation and growth [54,55]. The role of STAT2 and dysregulation. PIAS1 has been shown to modulate
STAT3 might not be fully redundant because STAT2 myogenesis also through the interaction with proteins
appeared to mediate principally the action of JAK2 on that can regulate myoblast differentiation, such as
hepatocyte growth factor expression, whereas the SnoN or Msx1 [59–61]. PIAS1 interacts with and
expression of IGF2 was mediated by both STAT2 and directly sumoylates SnoN, which increases the SnoN
STAT3 [49]. Taken together, these studies indicate that capacity to block myogenin gene expression and subse-
various members of the JAK/STAT family are quent cell differentiation [59,61]. In addition, PIAS1
involved in the regulation of muscle cell proliferation was also shown to interact with and sumoylate Msx1,
and differentiation through different partners and which is then capable of binding to the MyoD pro-
effectors, thereby exerting distinct actions throughout moter thus repressing MyoD gene expression [60].
myogenesis. It is not yet well known which ligands However, the precise role of PIAS1 in myogenic differ-
engage the JAK2/STAT2/STAT3 pathway during entiation remains debatable, because distinct pheno-
myogenic differentiation. Because IL-6 is expressed in types have been obtained after interfering with its
differentiating myoblasts, and it promotes their differ- expression [59,60]. Therefore, additional studies are
entiation and fusion [33,34], IL-6 (as well as LIF) [35] necessary to confirm the myogenic function of these
may be a potential trigger of these actions. molecules. Similarly, further investigation is necessary
A conclusion that can be deduced from the studies to decipher the function the SH2-containing phospha-
described above is that the JAK1/STAT1/STAT3 tase family inhibitors of JAK/STAT. Although SH2-
pathway needs to be tuned down for cessation of myo- containing phosphatase has been associated with
blast proliferation and commencement of differentia- myoblast differentiation [62], siRNA knockdown did
tion. Consistent with this idea, the kinase activity of not affect the activity of the JAK1/STAT1/STAT3
JAK1 is reduced upon differentiation [48]. Three fami- pathway during the differentiation process [50].
lies of regulators of JAK/STAT signaling are known: Finally, evidence that other IL-6 family members
the SOCS family of proteins, the protein inhibitor of oncostatin M and cardiotrophin-1 are also active in
activated STAT (PIAS) family of proteins and the myogenesis in vitro and in vivo was recently provided
SH2-containing phosphatase family of proteins [56]. [51,63]. Oncostatin M was shown to inhibit myoblast
These proteins target distinct members of the JAK/ differentiation by activating the JAK1/STAT1/STAT3
STAT pathway in distinct cellular compartments. pathway. STAT1 can interact with, and repress the
SOCS1 and SOCS3 target JAK1 and gp130, respec- transcriptional activity of, MEF2 in vitro. Further-
tively, near the plasma membrane to prevent cytoplas- more, prolonged expression of oncostatin M in injured
mic STATs from being activated, whereas PIAS1 skeletal muscles resulted in defective regeneration. By

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contrast, treatment of myoblasts with cardiotrophin-1 the onset of exercise [73,74]. This finding suggested
inhibited their differentiation. However, this action muscle contraction as such would lead to an increase
was preferentially mediated through activation of in IL-6 transcriptional rate within the nuclei from
MEK/ERK signaling [51,63], which in turn might myocytes. Further evidence that contracting muscle
interfere with activation of critical myogenic regulatory fibers themselves were a source of IL-6 mRNA and
factors. These findings suggest that cardiotrophin-1 protein was achieved by analysis of biopsies from the
and oncostatin M may be implicated in the mainte- human vastus lateralis using in situ hybridization and
nance of the undifferentiated state in muscle progeni- immunohistochemistry techniques [75]. Other studies
tor cells, in collaboration with the proliferative actions applied the microdialysis technique and demonstrated
of IL-6 and LIF. Collectively, these data suggest that that the concentration of IL-6 within the contracting
several members of the IL-6 family of cytokines con- skeletal muscle may be 5–100-fold higher than the lev-
tribute to myogenesis in vitro and muscle regeneration els found in the circulation and that IL-6 appears to
and growth in vivo, acting at distinct stages of these accumulate within the contracting muscle fibers as well
processes in a timely and regulated fashion, through as in the interstitium during exercise [76]. The simulta-
distinct signaling pathways and effectors. neous measurement of arteriovenous IL-6 concentra-
tions and blood flow across the leg in humans has
demonstrated that large amounts of IL-6 are released
Local and systemic beneficial
into the circulation from the exercising leg [77].
metabolic effects of muscle-derived
Studies on human myoblasts [78,79] and human cul-
IL-6
tured myotubes [80] have, more recently, added sub-
During the past decade, skeletal muscle has been iden- stantial findings to the initial human physiological
tified as a secretory organ. In accordance, we have experiments. It has been shown that IL-6 is locally
suggested that cytokines and other peptides that are and transiently produced by growing murine myofibers
produced, expressed and released by muscle fibers and and associated satellite cells [21]. In addition, IL-6 is
exert either autocrine, paracrine or endocrine effects released from human primary muscle cell cultures from
should be classified as ‘myokines’ [4,64,65]. Although healthy individuals [81,82] and from patients with
myostatin was the first muscle-derived peptide that ful- type 2 diabetes [82]. Moreover, IL-6 is upregulated in
filled the criteria for a myokine, IL-6 was the first human primary muscle cells following electrical stimu-
myokine that was found to be secreted into the blood lation in vitro [83,84].
stream in response to muscle contractions [1]. Interest- Skeletal muscle production and release of IL-6 are
ingly, IL-6 was serendipitously discovered as a myoki- regulated both by muscle contraction as well as by
ne because of the observation that it increased in an substrate availability. Thus, when muscle glycogen is
exponential fashion proportional to the length of exer- low, more IL-6 is produced and released during exer-
cise and the amount of muscle mass engaged in the cise. This finding is compatible with the idea that mus-
exercise (for review see Ref. [66]). Circulating levels of cle-derived IL-6 works as an energy sensor [85,86]. In
IL-6 may increase up to 100-fold, although it should accordance, enhanced glucose availability and training
be said that less dramatic increases are more frequent. adaptation attenuate the exercise-sensitive increase in
It is important to highlight the fact that the increase IL-6 plasma concentration [85,87]. The finding that
of IL-6 in the circulation occurs during dynamic exer- IL-6 is released into the blood stream during exercise
cise without any sign of muscle damage [66]. More- and that this release is dependent on substrate avail-
over, the IL-6 response to exercise is not preceded by ability during exercise, suggested that IL-6 plays a role
an increase TNF a. This finding was in contrast to the in maintaining energy status during exercise. To study
common belief that the increase in IL-6 during exercise this hypothesis, recombinant human IL-6 was infused
represented a classic acute-phase response initiated by into healthy volunteers and glucose and lipid metabo-
local damage in the working muscles [67]. It was lism were studied using stabile isotopes [88–91]. These
hypothesized that macrophages were responsible for studies were combined with animal models, studies on
this increase [68], however, early studies clearly demon- isolated muscle as well as cellular studies, and showed
strated that immune cells were not the source of origin that physiologically relevant levels of IL-6 have impor-
of IL-6 [69–71]. It was also made clear that the liver tant acute metabolic effects. One study clearly showed
clears, rather than secretes, IL-6 during exercise [72]. that IL-6 is an endocrine myokine with cardinal bio-
Human studies revealed that the nuclear transcrip- logical across organs because it contributes to hepatic
tion rate for IL-6, as well as the IL-6 mRNA levels glucose production during exercise [92]. It was also
are rapidly and markedly increased immediately after discovered that IL-6 enhances fat oxidation in skeletal

4136 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
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muscle via an activation of AMP-activated protein the underlying cytokine network, could participate in
kinase [91,93,94] and enhances lipolysis in skeletal the development of the multifactorial syndrome of
muscle with little effect on adipose tissue [88]. cachexia have been thoroughly studied [99–102].
Acute administration of IL-6 enhances glucose Cachexia is often associated with cancer and other
uptake and translocation of the glucose transporter pathological conditions and not surprisingly the first
GLUT4 from intracellular compartments to the experimental evidences for a possible negative role of
plasma membrane and enhances insulin-stimulated glu- IL-6 in the control of muscle mass were obtained
cose uptake in humans [91]. It has recently been shown using animal models of inflammation and tumor
that IL-6 transgenic mice with sustained elevated circu- induced cachexia. In these models, circulating IL-6
lating IL-6 display enhanced central leptin action and concentrations were elevated, along with those of
improved nutrient homeostasis leading to protection other inflammatory mediators. Inhibiting IL-6 signal-
from diet-induced obesity [95]. Human studies show ing by neutralizing antibodies was shown to have a
that IL-6 mediates anti-inflammatory effects and inhib- protective effect on body weight loss [103,104]. How-
its lipopolysaccharide-induced increase in circulating ever, whether IL-6 signaling is sufficient and/or has a
TNF [4,64]. Moreover, IL-6 signaling in liver-paren- direct role in the induction of muscle atrophy
chymal cells suppresses hepatic inflammation and remains controversial. We focus this section in
improves systemic insulin action in mice [96]. Thus, reviewing the research on the catabolic effects of
IL-6 can induce both pro- and anti-inflammatory IL-6 on skeletal muscle and the possible mechanisms
effects. involved.
Evidence is emerging that IL-6 is also playing a
major role in pancreatic b-cell metabolism and insulin
Effects of IL-6 on muscle protein synthesis and
secretion. Bouzakri et al. clearly suggested a new route
degradation rates
of communication between skeletal muscle and b cells
that is modulated by insulin resistance and could con- The rate of protein breakdown in isolated rat muscles
tribute to normal b-cell functional mass in healthy sub- exposed to recombinant IL-6 [105,106], or after injec-
jects, as well as to the decrease seen in type 2 diabetes tion of IL-6 into normal mice [107], was found to be
[97]. In another study, Ellingsgaard et al. showed that unaltered. Similarly, no effect of exogenous IL-6 on
the exercise-induced glucagon-like peptide-1 (a hor- the proteolytic rate of rat and murine myotubes could
mone that induces insulin secretion) response was be demonstrated [108], which agrees with the
dependent upon muscle-derived IL-6 [98]. Hence IL-6 unchanged net muscle protein catabolism in mice after
mediates cross-talk between insulin-sensitive tissues, the 1 week of daily IL-6 administration [109]. These data
gut and pancreatic islets to adapt to changes in insulin are also supported by the lack of ubiquitin gene upreg-
demand by increasing glucagon-like peptide-1 secretion. ulation in muscle after infusion of a single dose of
Collectively, these data show that IL-6 is produced IL-6 to rats, contrary to the effects observed by treat-
by contracting skeletal muscle and play important ing the animals with inflammatory cytokines like
roles in regulating metabolism in other organs. To TNFa, interferon-c or IL-1 [110].
view skeletal muscle as a secretory organ provides a In contrast to these data, increased muscle proteoly-
conceptual basis and a whole new paradigm for under- sis was found after administration of high doses or
standing how muscles communicate with other organs long-term exposure to IL-6 in rats or mice [106,111].
such as adipose tissue, liver, pancreas, bones and This is the case for transgenic mice engineered to over-
brain, explaining why lack of physical activity appears express elevated circulating levels of human IL-6 which
to be a cause of a whole network of diseases, including display severe muscle atrophy by the age of 10 weeks,
cardiovascular diseases, type 2 diabetes, cancer and together with myofiber-intrinsic activation of the lyso-
osteoporosis [65]. somal enzymes cathepsins B and L and increased pro-
teosomal subunit expression [111,112]. Because
blockade of IL-6 signaling by sustained treatment with
Negative regulation of muscle mass
a mouse IL-6R antibody completely reversed the mus-
by IL-6
cular changes reported in IL-6 transgenic mice [112]
and reduced muscle atrophy of tumor-bearing wild-
Is IL-6 signaling directly involved in muscle
type mice [113], it was proposed that IL-6 might have
atrophy?
a permissive role in the development of skeletal muscle
Since the early 1990s, the implication that elevated degradation and body weight reduction when other
systemic IL-6 levels, together with the complexity of circulating cytokines were also present [114,115].

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IL-6 myokine signaling in skeletal muscle ~oz-C
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It is important to note that differential effects of demand for amino acids for acute-phase protein syn-
IL-6 on muscle have also been reported depending on thesis is elevated, and where the muscle catabolic rates
the dose applied and the manner of administration is increased, such as in patients with end-stage renal
[116–118]. For example, a significant decrease in myo- disease, IL-6 could be released by the muscle indepen-
fibrillar protein content was induced in rats by local dent of amino acid availability. IL-6 would then be
IL-6 infusion (0.7 pg
muscle 1
h 1) [116]. This related with muscle protein degradation, supporting
approach produced a local IL-6 concentration mimick- the notion that IL-6 in this context functions as a
ing the muscle IL-6 concentrations reached after stren- prominent protein catabolic signal [121]. In summary,
uous exercise in humans (22 ng
L 1) [119], which did no proatrophic role for IL-6 could be experimentally
not induce systemic effects on circulating IL-6 levels, corroborated in a short time period and/or with low
nor on body and heart mass. Low systemic doses of dose treatments. Alternatively, persistent and systemic
IL-6 (50 lg
kg 1
day 1) infused into rats did not cause IL-6 levels may be necessary for the induction of cata-
a significant reduction of fiber size or muscle weight, bolic effects and muscle wasting, with the possible par-
or altered contractile properties of the diaphragm mus- ticipation of other mediators.
cle [117]. However, much higher doses of IL-6
(250 lg
kg 1
day 1) significantly decreased limb mus-
Indirect effects of IL-6 on muscle atrophy:
cle weight by 15% and reduced myofiber size in both
interference with the growth hormone/insulin-
fast and slow muscle types, affecting particularly the
like growth factor-1 pathway
gastrocnemius muscle. Because this treatment also
induced severe cardiovascular alterations, it is not Another layer of complexity of the negative effects of
clear to what extent peripheral skeletal muscle atrophy IL-6 on muscle growth is represented by its interference
was secondary to myocardial failure and/or any meta- with the growth hormone/insulin-like growth factor-1
bolic actions of the cytokine [117]. (GH/IGF1) axis. Indeed, reduced growth was observed
However, IL-6 may not be required for accelerated in several transgenic mouse models overexpressing
muscle protein degradation, even in circumstances in human IL-6 [122]. These mice possess high circulating
which the cytokine is found at high circulating concen- levels of IL-6 from early stages of life, have normal
trations. For example, muscles of IL-6 knockout and growth hormone levels, but noticeably reduced serum
wild-type mice showed similar increases in total and IGF1 levels and enhanced muscle SOCS3 mRNA
myofibrillar protein breakdown rates in an experimen- expression. Short-term IL-6 administration to wild-type
tal model of sepsis, and no increase in muscle protein mice and humans also reduced circulating IGF1 levels
breakdown rates were found in wild-type mice sub- [122,123]. Similarly, neutralization of IL-6 activities in
jected to a sterile turpentine abscess model that IL-6 transgenic mice rescued the circulating IGF1 lev-
increased IL-6 plasma concentration by 100-fold [107]. els and fully restored growth, reinforcing the mechanis-
In humans, the effects of IL-6 may also depend on tic connection between high IL-6 and low IGF1 levels
the particular context of other systems and organs. In in plasma [124]. IGF1 is produced primarily by the
healthy human subjects, infusion of a dose of recombi- liver and is transported in the blood bound to IG-
nant IL-6 (30 lg
h 1) that mimics the IL-6 plasma FBP3, the most abundant circulating IGF-binding pro-
concentrations after intense prolonged exercise, slightly tein, in heterotrimeric complexes that also contain a
increased net muscle protein breakdown [120]. How- glycoprotein termed acid-labile subunit [125]. When
ever, the most surprising effects were that this IL-6 carefully examining transgenic animals overexpressing
administration reduced the concentration of arterial IL-6, which also have reduced circulating IGF1 levels,
amino acids by 20–40%, despite their net release from liver IGF1 production and the amount of functional
the muscle, and that there was an ~ 50% reduction in serum acid-labile subunit were found to be unaffected.
total muscle protein turnover. These effects could be However, circulating IGFBP3 was markedly reduced,
ascribed to an increased demand for circulating amino which was associated with its increased proteolysis
acids by other organs, leading secondarily to their [126]. Because a similar reduction of IGFBP3 levels
depletion in plasma. In turn, this would lead to a were found in wild-type mice treated with exogenous
decrease in intracellular synthesis and breakdown of IL-6, it was concluded that an impairment in the for-
muscle proteins, with a minimal net predominance of mation of stable ternary complexes of IGF1/IGFBP3/
protein degradation. Thus, in a healthy state, IL-6 acid-labile subunit negatively affected the half-life of
might function as a strong metabolic signal rather than IGF1 in the blood and increased its clearance. The
directly controlling protein turnover rates in the mus- mechanisms by which IL-6 may stimulate IGFBP3 pro-
cle [120]. By contrast, in situations in which the tein degradation have not been clarified.

4138 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
 ~oz-C
P. Mun anoves et al. IL-6 myokine signaling in skeletal muscle

Importantly, studies in humans revealed that short- These changes were associated with a concomitant
term maximal exercise, which is associated with muscle reduction of circulating levels of IL-6 and IL-1band
release of IL-6, or acute IL-6 infusion resembling the increased local expression of IGF1, SOCS3, atrogin,
concentrations of IL-6 in serum observed after exer- TNFa and its receptor.
cise, did not affect circulating IGFBP3 levels or its The interpretation of these results with respect to
proteolytic degradation rate [123,127,128]. On the con- the control of muscle degradation pathways is difficult
trary, reduced circulating IGF1 and IGFBP3 levels to make unequivocally. Increased muscle IGF1 levels
were confirmed in patients with chronically elevated [133] and STAT3 phosphorylation were also observed
serum IL-6 [122,126]. Overall, these results again sup- in models of hypertrophy [133,134], whereas S6K1
port strikingly different actions of acute and persis- activation appeared dispensable for normal protein
tently circulating IL-6 on the interference with IGF1 synthesis and degradation rates, as well as polysome
levels. IGF1 levels may, in turn, influence muscle IL-6 formation in skeletal muscle [135]. TNFa has been
production. Indeed, sustained IGF1 administration to shown to upregulate atrogin-1 expression in skeletal
mice prevented sepsis-induced muscle atrophy and muscle via p38 MAPK-mediated phosphorylation of
inhibited the muscle IL-6 mRNA upregulation in this C/EBPb [136–138]. Thus, indirect local upregulation of
model [129]. Finally, an indirect contribution to muscle TNFa and its receptor might have contributed to the
atrophy by inflammatory cytokines occurring via the reduced myofibrillar protein content after local unilat-
hypothalamic–pituitary–adrenal axis should also be eral IL-6 infusion into rat muscles [118].
considered in chronic conditions. Inflammatory media- Whereas reduced muscle STAT5 levels may indicate
tors acting on the central nervous system can trigger a local low growth hormone signal activity [139], the
catabolic program in skeletal muscle leading to severe direct role for SOCS3 in atrophy is not yet clear, since
atrophy, independent of the actions of the cytokines its expression also increases in paradigms associated
on the muscle [130]. These effects would be mediated with muscle hypertrophy [133] and exercise training
in part by a glucocorticoid response, as muscle atro- [140], and decreases in unloading-induced atrophy
phy is inhibited in adrenalectomized animals after cen- models [141]. Augmented SOCS3 expression was
tral nervous system inflammatory stimulus. The reported in experimental cancer-induced muscle wast-
contribution of IL-6-induced signaling to this newly ing in mice undergoing an exacerbated proteolysis
described central nervous system-mediated atrophy leading to a 25% weight loss of limb muscles [142].
remains to be fully explored. Interestingly, in this model, the SOCS3 protein level in
cachectic muscles was unchanged or even reduced in
the more atrophic muscles versus muscles of control
Downstream effectors of IL-6 in muscle atrophy
mice despite SOCS3 mRNA upregulation. This finding
The specific mediators of IL-6 action in muscle atro- was interpreted as a JAK/STAT-driven increase in
phy have not been characterized, but some molecules proteolytic degradation of SOCS3, which would in
have been proposed for these proatrophic effects. IL-6 turn lead to persistent STAT3 signaling in the muscle
overexpression in transgenic mice [131], or in normal because SOCS3 inhibits STAT3. In this case, STAT3
mice by intramuscular electroporation of plasmid is the primary mediator of muscle wasting [143].
DNA [132], decreased muscle mass and induced Indeed, transfection of a plasmid expressing consti-
SOCS3 gene expression, suggesting a putative involve- tutively active STAT3 into normal mouse muscle
ment of SOCS3 in muscle atrophy. In agreement with induced a significant reduction of myofiber cross-sec-
these findings, infusion of IL-6 in muscle for 2 weeks tional area, whereas a dominant negative mutant of
induced STAT3 activation and SOCS3 transcription, STAT3, or electroporation of a STAT3 short hairpin,
correlating with a local reduction of myofibrilar pro- prevented the atrophy induced by injection of Chinese
tein content [116]. SOCS3, in turn, might downregulate hamster ovary cells overexpressing IL-6 in athymic
IL-6 signaling in this system. Surprisingly, the nude mice and in the C26 adenocarcinoma mouse
expression of muscle ubiquitin ligases atrogin-1 and model [143]. These data suggest that persistent STAT3
MURF-1 was not affected in the later study, but IL-6 signaling may play an important pathogenic role in
treatment reduced the phosphorylation of ribosomal the development of muscle wasting in some disease
S6K1 and STAT5 proteins and increased muscle IGF1 states through yet uncharacterized mechanisms. Inter-
expression [116]. In a similar approach, local low doses estingly in this regard, a recent study has reported that
of IL-6 (0.0014 pg
mg muscle 1
h 1) infused for activation of STAT3 is involved in the regulation of
2 weeks into rat muscle decreased myofibrillar protein autophagy [144]. The nonreceptor tyrosine kinase Fyn
content with respect to the contralateral muscles [118]. would be activated selectively in the fast-glycolytic

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IL-6 myokine signaling in skeletal muscle ~oz-C
P. Mun anoves et al.

fibers in the fed state, inducing phosphorylation of inhibiting IGF1-dependent signaling [138]. In this par-
STAT3 which, in turn, would inhibit expression of the ticular example, an interorgan pathway can be delin-
class 3 phosphatidylinositol kinase Vps34 protein, eated, with liver controlling muscle wasting and IL-6
which is necessary for autophagosome formation [144]. having a necessary, but insufficient role, because the
Thus, according to this model, persistent STAT3 acti- action of other inflammatory mediators is also
vation might result in chronic inhibition of macroauto- required to trigger muscle atrophy.
phagy which would lead to muscle atrophy [145]. Hyperactivation of IL-6/STAT3 signaling in muscle
may also stimulates the synthesis and systemic release
of acute-phase response proteins such as SAA and
Synergy of IL-6 with other molecules and
fibrinogen [142], which may function as an amplifying
autocrine IL-6 upregulation
mechanism for catabolic signals in the muscle, turning
Circulating IL-6 may synergize with other molecules to muscle into a key player in innate immunity with the
induce muscular atrophy in some disease states. For capacity of producing fivefold more protein than the
instance, activation of the renin–angiotensin system, liver, considering that skeletal muscle represents
which is commonly found to be induced in congestive ~ 40% of total body weight.
heart failure or chronic kidney disease, is known to IL-6 signaling in skeletal muscle may induce activa-
cause severe muscle degradation. Indeed, increased tion of its own transcription in a sort of positive feed-
muscle proteolysis is reproduced experimentally if back loop. Autocrine upregulation of IL-6 production
angiotensin II (Ang II) is infused into rodents [146]. is supported by the observation of increased muscle
This Ang II effect, which is associated with low levels IL-6 mRNA expression after infusion of recombinant
of circulating and muscle-intrinsic IGF1, as well as IL-6 in humans [149] and in cultured mouse and
downregulation of active AKT and caspase 3, can be human myotubes [150]. This regulatory mechanism
rescued by muscle overexpression of IGF1 [146]. IGF1 may involve Ca2+-dependent pathways and increased
stimulation prevents Ang II-induced atrophy by acti- mRNA stabilization [150]. SOCS3 mRNA was signifi-
vating AKT and inhibiting Foxo-1-dependent activa- cantly increased in rat muscles after a treadmill run-
tion of atrogin-1 [147]. Because the Ang II receptor is ning training program, together with IL-6 expression
not expressed by skeletal muscle [138], the proatrophic and enhanced NF-jB activity [140]. In vitro studies
effects of Ang II must be indirect, and IL-6 has been using the IL-6 promoter linked to the luciferase repor-
postulated as a significant mediator. Administration of ter gene suggested a positive feedback loop by which
Ang II to wild-type mice induced elevated plasma IL-6 exercise-induced IL-6 may activate SOCS3 expression
by release from the liver, whereas Ang II infusion to and sustain its own expression through NF-jB-depen-
IL-6-deficient animals did not cause muscle atrophy. dent pathways [140], thus suggesting the existence of
Nor did it reduce AKT activity, activated caspase 3, both positive and negative cross-regulatory loops. This
ubiquitin–proteasome-dependent pathways or elevated mechanism is consistent with the reported NF-jB acti-
SOCS3 levels. SOCS3, which is induced by IL-6, has vation in rat muscles by exercise [151] and the recent
been shown to inhibit insulin-dependent signaling by findings in humans showing that NF-KB DNA-binding
promoting the proteasomal degradation of insulin activity to the IL-6 promoter increases transiently after
receptors [148]. However, IL-6 alone is not sufficient exercise [152]. Whether similar amplifying mechanisms
to mediate the atrophic actions of Ang II on muscle may be functional in accelerated catabolic conditions
tissue. Elevated levels of the acute-phase protein serum deserves further investigation.
amyloid A (SAA), also induced in liver by Ang II,
synergistically acts with IL-6 to induce SOCS3 protein
Conclusion and perspectives
expression up to the threshold level required for AKT
pathway inhibition. In vitro experiments confirmed Since the discovery of IL-6, many investigations have
that neither IL-6 nor SAA alone induce significant explored the role of this pleiotropic cytokine and other
changes in protein degradation or myotube size, nor members of the IL-6 cytokine family on skeletal mus-
were they able to activate the ubiquitin–proteasome cle. It appears consistently in the literature that IL-6,
system. However, the combination of IL-6 and SAA produced locally by different cell types, has a positive
induced myotube atrophy and stimulated proteolysis impact on the proliferative capacity of muscle stem
via proteasomal activation. Taken together, these data cells. This physiological mechanism functions to pro-
indicate that Ang II stimulates liver-dependent sys- vide enough muscle progenitors in situations that
temic release of IL-6 and SAA that synergistically tar- require a high number of these cells, such as during
get muscle cells to induce muscle proteolysis by the processes of muscle regeneration and hypertrophic

4140 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
 ~oz-C
P. Mun anoves et al. IL-6 myokine signaling in skeletal muscle

growth after an acute stimulus. IL-6 is also the found- IL-6 levels, which can be reproduced experimentally in
ing member of the myokine family of muscle-produced different animal model-systems. In such situations,
cytokines. Indeed, muscle-produced IL-6 after repeated IL-6 actions are coupled with increased muscle wast-
contractions also has important autocrine and para- ing, very often acting in combination with other mole-
crine benefits, acting as a myokine, in regulating cules or functioning indirectly to promote atrophy (for
energy metabolism, controlling, for example, metabolic example, by inhibiting IGF1-dependent signaling). The
functions and stimulating glucose production (see direct action of IL-6 as a regulator of atrophy has not
Fig. 1 for an overview of IL-6 production, mechanisms been unanimously corroborated by experimental find-
of action and effects). It is important to note that ings. Future studies will take advantage of the avail-
these positive effects of IL-6 and other myokines are able technology that allows the selective interference
normally associated with its transient production and with IL-6 production, IL-6 receptor and downstream
short-term action. The identification of new myokines signaling in specific cell types at a desired experimental
will potentially serve as novel targets for the treatment stage to fully decipher the contribution of the cytokine
of metabolic diseases. in different contexts. This knowledge will also poten-
On the contrary, persistent inflammatory conditions tially allow selective interference of the deleterious
and some types of cancer and other chronic disease actions of IL-6 in pathological contexts and promoting
states are associated with long-lasting elevated systemic the beneficial effects of IL-6 for therapeutic purposes.

Muscle
Adipose Myofiber
contraction
tissue IL-6
Satellite
IL-6
cell

gp130

gp130
IL-6R
IL-6
IL-6
P
JAK SOCS
Cytoplasm

P
STAT3 STAT3

Chronic IL-6
inflammation IL-6
Tissue injury Nucleus
STAT3-dependent
IL-6 P
gene transcription
IL-6 PIAS STAT3

Myoblasts
Blood
vessels
IL-6 IL-6

Liver
Growth
IL-6 Atrophy
IL-6 Proliferation
Differentiation
Inflammatory Survival
cells Apoptosis

Myotube

Fig. 1. Integrative representation of IL-6 production, signaling mechanisms and local and systemic effects on skeletal muscle and peripheral
tissues. (Left) Myofiber released IL-6 after muscle contraction, satellite cell and local inflammatory cell-derived IL-6 after tissue injury impact
positively on muscle regeneration and growth by stimulating myoblast proliferation and myotube formation. Muscle-derived IL-6 also has a
positive impact on the metabolism of muscle and peripheral tissues, for example, by stimulating glucose availability during exercise and
thus acting as an ‘energy sensor’. In chronic inflammatory situations, when circulating IL-6 concentration is persistently elevated, a muscle
procatabolic effect of the cytokine (pink arrows) has been described by either direct and/or indirect mechanisms (see the text for details).
(Right) IL-6-signaling model. The complex of IL-6 and its receptor (IL-6R) binds to the ubiquitously expressed transmembrane protein gp130
homodimer that transmits the signal intracellularly. The major downstream signaling uses the JAK/STAT3 pathway. Once phosphorylated in
the cytoplasm, STAT3 migrates to the nucleus and activates transcription on target gene promoters. Members of the SOCS family of
proteins and the PIAS family are inhibitors of the JAK/STAT pathway at different levels. The IL-6-induced signaling exerts different effects
on distinct cell types and tissues.

FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS 4141
IL-6 myokine signaling in skeletal muscle ~oz-C
P. Mun anoves et al.

Acknowledgements 14 Sartorelli V & Caretti G (2005) Mechanisms

underlying the transcriptional regulation of skeletal
The authors acknowledge funding from EU-FP7 myogenesis. Curr Opin Genet Dev 15, 528–535.
(Myoage) and MICINN (SAF2009-09782, FIS-PS09/ 15 Tapscott SJ (2005) The circuitry of a master switch:
01267, SAF2012-38547, PLE2009-0124, CIBERNED), myod and the regulation of skeletal muscle gene
AFM, Fundacion Marat o-TV3, MDA, EU-FP7 (Opti- transcription. Development 132, 2685–2695.
stem and Endostem). The Centre of Inflammation and 16 Lluis F, Perdiguero E, Nebreda AR & Munoz-
Metabolism (CIM) is supported by a grant from the Canoves P (2006) Regulation of skeletal muscle gene
Danish National Research Foundation (DNRF55). expression by p38 MAP kinases. Trends Cell Biol 16,
36–44.
17 Perdiguero E, Sousa-Victor P, Ballestar E & Munoz-
References Canoves P (2009) Epigenetic regulation of myogenesis.
1 Pedersen BK & Febbraio MA (2008) Muscle as an Epigenetics 4, 541–550.
endocrine organ: focus on muscle-derived interleukin-6. 18 Guasconi V & Puri PL (2009) Chromatin: the interface
Physiol Rev 88, 1379–1406. between extrinsic cues and the epigenetic regulation of
2 Broholm C & Pedersen BK (2010) Leukaemia muscle regeneration. Trends Cell Biol 19, 286–294.
inhibitory factor – an exercise-induced myokine. Exerc 19 Dilworth FJ & Blais A (2011) Epigenetic regulation of
Immunol Rev 16, 77–85. satellite cell activation during muscle regeneration.
3 Broholm C, Laye MJ, Brandt C, Vadalasetty R, Stem Cell Res Ther 2, 18.
Pilegaard H, Pedersen BK & Scheele C (2011) LIF is a 20 Spangenburg EE & Booth FW (2006) Leukemia
contraction-induced myokine stimulating human inhibitory factor restores the hypertrophic response to
myocyte proliferation. J Appl Physiol 111, 251–259. increased loading in the LIF(-/-) mouse. Cytokine 34,
4 Pedersen BK & Febbraio MA (2012) Muscles, exercise 125–130.
and obesity: skeletal muscle as a secretory organ. Nat 21 Serrano AL, Baeza-Raja B, Perdiguero E, Jardi M &
Rev Endocrinol 8, 457–465. Munoz-Canoves P (2008) Interleukin-6 is an essential
5 Hirano T (1998) Interleukin-6 and its receptor: ten regulator of satellite cell-mediated skeletal muscle
years later. Int Rev Immunol 16, 249–284. hypertrophy. Cell Metab 7, 33–44.
6 Rose-John S, Scheller J, Elson G & Jones SA (2006) 22 Guerci A, Lahoute C, Hebrard S, Collard L,
Interleukin-6 biology is coordinated by membrane- Graindorge D, Favier M, Cagnard N, Batonnet-
bound and soluble receptors: role in inflammation and Pichon S, Precigout G, Garcia L et al. (2012) Srf-
cancer. J Leukoc Biol 80, 227–236. dependent paracrine signals produced by myofibers
7 Scheller J & Rose-John S (2006) Interleukin-6 and its control satellite cell-mediated skeletal muscle
receptor: from bench to bedside. Med Microbiol hypertrophy. Cell Metab 15, 25–37.
Immunol 195, 173–183. 23 Horsley V, Jansen KM, Mills ST & Pavlath GK
8 Kopf M, Baumann H, Freer G, Freudenberg M, (2003) IL-4 acts as a myoblast recruitment factor
Lamers M, Kishimoto T, Zinkernagel R, Bluethmann during mammalian muscle growth. Cell 113, 483–494.
H & Kohler G (1994) Impaired immune and acute- 24 Prokopchuk O, Liu Y, Wang L, Wirth K,
phase responses in interleukin-6-deficient mice. Nature Schmidtbleicher D & Steinacker JM (2007) Skeletal
368, 339–342. muscle IL-4, IL-4Ralpha, IL-13 and IL-13Ralpha1
9 Blatteis CM & Sehic E (1998) Cytokines and fever. expression and response to strength training. Exerc
Ann N Y Acad Sci 840, 608–618. Immunol Rev 13, 67–75.
10 Lepper C, Conway SJ & Fan CM (2009) Adult 25 Kurek JB, Bower JJ, Romanella M, Koentgen F,
satellite cells and embryonic muscle progenitors have Murphy M & Austin L (1997) The role of leukemia
distinct genetic requirements. Nature 460, 627–631. inhibitory factor in skeletal muscle regeneration.
11 Yin H, Price F & Rudnicki MA (2013) Satellite cells Muscle Nerve 20, 815–822.
and the muscle stem cell niche. Physiol Rev 93, 23–67. 26 Barnard W, Bower J, Brown MA, Murphy M &
12 Rocheteau P, Gayraud-Morel B, Siegl-Cachedenier I, Austin L (1994) Leukemia inhibitory factor (LIF)
Blasco MA & Tajbakhsh S (2012) A subpopulation infusion stimulates skeletal muscle regeneration after
of adult skeletal muscle stem cells retains all injury: injured muscle expresses lif mRNA. J Neurol
template DNA strands after cell division. Cell 148, Sci 123, 108–113.
112–125. 27 Kurek JB, Nouri S, Kannourakis G, Murphy M &
13 Puri PL & Sartorelli V (2000) Regulation of muscle Austin L (1996) Leukemia inhibitory factor and
regulatory factors by DNA-binding, interacting interleukin-6 are produced by diseased and
proteins, and post-transcriptional modifications. J Cell regenerating skeletal muscle. Muscle Nerve 19,
Physiol 185, 155–173. 1291–1301.

4142 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
 ~oz-C
P. Mun anoves et al. IL-6 myokine signaling in skeletal muscle

28 Zhang C, Li Y, Wu Y, Wang L, Wang X & Du J analysis of p38 MAP kinases in myogenesis:

(2013) Interleukin-6/signal transducer and activator of fundamental role of p38alpha in abrogating myoblast
transcription 3 (STAT3) pathway is essential for proliferation. EMBO J 26, 1245–1256.
macrophage infiltration and myoblast proliferation 41 Bennett AM & Tonks NK (1997) Regulation of
during muscle regeneration. J Biol Chem 288, distinct stages of skeletal muscle differentiation by
1489–1499. mitogen-activated protein kinases. Science 278, 1288–
29 Joe AW, Yi L, Natarajan A, Le Grand F, So L, Wang 1291.
J, Rudnicki MA & Rossi FM (2010) Muscle injury 42 Coolican SA, Samuel DS, Ewton DZ, McWade FJ &
activates resident fibro/adipogenic progenitors that Florini JR (1997) The mitogenic and myogenic actions
facilitate myogenesis. Nat Cell Biol 12, 153–163. of insulin-like growth factors utilize distinct signaling
30 Kami K & Senba E (1998) Localization of leukemia pathways. J Biol Chem 272, 6653–6662.
inhibitory factor and interleukin-6 messenger 43 Wu Z, Woodring PJ, Bhakta KS, Tamura K, Wen F,
ribonucleic acids in regenerating rat skeletal muscle. Feramisco JR, Karin M, Wang JY & Puri PL (2000)
Muscle Nerve 21, 819–822. p38 and extracellular signal-regulated kinases regulate
31 Kami K & Senba E (2002) In vivo activation of the myogenic program at multiple steps. Mol Cell Biol
STAT3 signaling in satellite cells and myofibers in 20, 3951–3964.
regenerating rat skeletal muscles. J Histochem 44 Guttridge DC, Albanese C, Reuther JY, Pestell RG &
Cytochem 50, 1579–1589. Baldwin AS Jr (1999) NF-kappaB controls cell growth
32 Gallucci S, Provenzano C, Mazzarelli P, Scuderi F & and differentiation through transcriptional regulation
Bartoccioni E (1998) Myoblasts produce IL-6 in of cyclin D1. Mol Cell Biol 19, 5785–5799.
response to inflammatory stimuli. Int Immunol 10, 45 Megeney LA, Perry RL, LeCouter JE & Rudnicki
267–273. MA (1996) bFGF and LIF signaling activates
33 Baeza-Raja B & Munoz-Canoves P (2004) p38 STAT3 in proliferating myoblasts. Dev Genet 19,
MAPK-induced nuclear factor-kappaB activity is 139–145.
required for skeletal muscle differentiation: role of 46 Spangenburg EE & Booth FW (2002) Multiple
interleukin-6. Mol Biol Cell 15, 2013–2026. signaling pathways mediate LIF-induced skeletal
34 Hoene M, Runge H, Haring HU, Schleicher ED & muscle satellite cell proliferation. Am J Physiol Cell
Weigert C (2013) Interleukin-6 promotes myogenic Physiol 283, C204–C211.
differentiation of mouse skeletal muscle cells: role of 47 Kataoka Y, Matsumura I, Ezoe S, Nakata S,
the STAT3 pathway. Am J Physiol Cell Physiol 304, Takigawa E, Sato Y, Kawasaki A, Yokota T,
C128–C136. Nakajima K, Felsani A et al. (2003) Reciprocal
35 Yang Y, Xu Y, Li W, Wang G, Song Y, Yang G, inhibition between MyoD and STAT3 in the
Han X, Du Z, Sun L & Ma K (2009) STAT3 induces regulation of growth and differentiation of myoblasts.
muscle stem cell differentiation by interaction with J Biol Chem 278, 44178–44187.
myoD. Cytokine 46, 137–141. 48 Sun L, Ma K, Wang H, Xiao F, Gao Y, Zhang W,
36 Spangenburg EE (2005) SOCS-3 induces myoblast Wang K, Gao X, Ip N & Wu Z (2007) JAK1–STAT1–
differentiation. J Biol Chem 280, 10749–10758. STAT3, a key pathway promoting proliferation and
37 Delling U, Tureckova J, Lim HW, De Windt LJ, preventing premature differentiation of myoblasts.
Rotwein P & Molkentin JD (2000) A calcineurin– J Cell Biol 179, 129–138.
NFATc3-dependent pathway regulates skeletal muscle 49 Wang K, Wang C, Xiao F, Wang H & Wu Z (2008)
differentiation and slow myosin heavy-chain JAK2/STAT2/STAT3 are required for myogenic
expression. Mol Cell Biol 20, 6600–6611. differentiation. J Biol Chem 283, 34029–34036.
38 Lu J, McKinsey TA, Zhang CL & Olson EN (2000) 50 Diao Y, Wang X & Wu Z (2009) SOCS1, SOCS3, and
Regulation of skeletal myogenesis by association of the PIAS1 promote myogenic differentiation by inhibiting
MEF2 transcription factor with class II histone the leukemia inhibitory factor-induced JAK1/STAT1/
deacetylases. Mol Cell 6, 233–244. STAT3 pathway. Mol Cell Biol 29, 5084–5093.
39 Serra C, Palacios D, Mozzetta C, Forcales SV, 51 Xiao F, Wang H, Fu X, Li Y, Ma K, Sun L, Gao X
Morantte I, Ripani M, Jones DR, Du K, Jhala US, & Wu Z (2011) Oncostatin M inhibits myoblast
Simone C et al. (2007) Functional interdependence at differentiation and regulates muscle regeneration. Cell
the chromatin level between the MKK6/p38 and Res 21, 350–364.
IGF1/PI3K/AKT pathways during muscle 52 Hunt LC, Upadhyay A, Jazayeri JA, Tudor EM &
differentiation. Mol Cell 28, 200–213. White JD (2011) Caspase-3, myogenic transcription
40 Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, factors and cell cycle inhibitors are regulated by
Ballestar E, Sousa-Victor P, Baeza-Raja B, Jardi M, leukemia inhibitory factor to mediate inhibition of
Bosch-Comas A, Esteller M et al. (2007) Genetic myogenic differentiation. Skeletal Muscle 1, 17.

FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS 4143
IL-6 myokine signaling in skeletal muscle ~oz-C
P. Mun anoves et al.

53 Fernando P, Kelly JF, Balazsi K, Slack RS & Butterworth DE (1998) Influence of mode and
Megeney LA (2002) Caspase 3 activity is required for carbohydrate on the cytokine response to heavy
skeletal muscle differentiation. Proc Natl Acad Sci exertion. Med Sci Sports Exerc 30, 671–678.
USA 99, 11025–11030. 68 Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC,
54 Glass DJ (2010) PI3 kinase regulation of skeletal Henson DA, Butterworth DE, Schmitt RL, Bailey
muscle hypertrophy and atrophy. Curr Top Microbiol EM, Warren BJ, Utter A & Davis JM (1997)
Immunol 346, 267–278. Carbohydrate and the cytokine response to 2.5 h of
55 Kaliman P, Canicio J, Shepherd PR, Beeton CA, running. J Appl Physiol 82, 1662–1667.
Testar X, Palacin M & Zorzano A (1998) Insulin-like 69 Ullum H, Haahr PM, Diamant M, Palmo J, Halkjaer-
growth factors require phosphatidylinositol 3-kinase to Kristensen J & Pedersen BK (1994) Bicycle exercise
signal myogenesis: dominant negative p85 expression enhances plasma IL-6 but does not change IL-1 alpha,
blocks differentiation of L6E9 muscle cells. Mol IL-1 beta, IL-6, or TNF-alpha pre-mRNA in BMNC.
Endocrinol 12, 66–77. J Appl Physiol 77, 93–97.
56 Wormald S & Hilton DJ (2004) Inhibitors of cytokine 70 Starkie RL, Angus DJ, Rolland J, Hargreaves M &
signal transduction. J Biol Chem 279, 821–824. Febbraio MA (2000) Effect of prolonged, submaximal
57 Leger B, Derave W, De Bock K, Hespel P & Russell exercise and carbohydrate ingestion on monocyte
AP (2008) Human sarcopenia reveals an increase in intracellular cytokine production in humans. J Physiol
SOCS-3 and myostatin and a reduced efficiency of Akt 528, 647–655.
phosphorylation. Rejuvenation Res 11, 163–175B. 71 Starkie RL, Rolland J, Angus DJ, Anderson MJ &
58 Trenerry MK, Carey KA, Ward AC, Farnfield MM & Febbraio MA (2001) Circulating monocytes are not
Cameron-Smith D (2008) Exercise-induced activation the source of elevations in plasma IL-6 and TNF-
of STAT3 signaling is increased with age. Rejuvenation alpha levels after prolonged running. Am J Physiol
Res 11, 717–724. Cell Physiol 280, C769–C774.
59 Hsu YH, Sarker KP, Pot I, Chan A, Netherton SJ & 72 Febbraio MA, Ott P, Nielsen HB, Steensberg A,
Bonni S (2006) Sumoylated SnoN represses Keller C, Krustrup P, Secher NH & Pedersen BK
transcription in a promoter-specific manner. J Biol (2003) Hepatosplanchnic clearance of interleukin-6 in
Chem 281, 33008–33018. humans during exercise. Am J Physiol Endocrinol
60 Lee H, Quinn JC, Prasanth KV, Swiss VA, Metab 285, E397–E402.
Economides KD, Camacho MM, Spector DL & 73 Keller C, Steensberg A, Pilegaard H, Osada T, Saltin
Abate-Shen C (2006) PIAS1 confers DNA-binding B, Pedersen BK & Neufer PD (2001) Transcriptional
specificity on the Msx1 homeoprotein. Genes Dev 20, activation of the IL-6 gene in human contracting
784–794. skeletal muscle: influence of muscle glycogen content.
61 Wrighton KH, Liang M, Bryan B, Luo K, Liu M, FASEB J 15, 2748–2750.
Feng XH & Lin X (2007) Transforming growth factor- 74 Steensberg A, Keller C, Starkie RL, Osada T,
beta-independent regulation of myogenesis by SnoN Febbraio MA & Pedersen BK (2002) IL-6 and TNF-
sumoylation. J Biol Chem 282, 6517–6524. alpha expression in, and release from, contracting
62 Kontaridis MI, Eminaga S, Fornaro M, Zito CI, human skeletal muscle. Am J Physiol Endocrinol
Sordella R, Settleman J & Bennett AM (2004) SHP-2 Metab 283, E1272–E1278.
positively regulates myogenesis by coupling to the Rho 75 Hiscock N, Chan MH, Bisucci T, Darby IA &
GTPase signaling pathway. Mol Cell Biol 24, 5340–5352. Febbraio MA (2004) Skeletal myocytes are a source of
63 Miyake T, Alli NS, Aziz A, Knudson J, Fernando P, interleukin-6 mRNA expression and protein release
Megeney LA & McDermott JC (2009) Cardiotrophin-1 during contraction: evidence of fiber type specificity.
maintains the undifferentiated state in skeletal FASEB J 18, 992–994.
myoblasts. J Biol Chem 284, 19679–19693. 76 Rosendal L, Sogaard K, Kjaer M, Sjogaard G,
64 Pedersen BK (2011) Exercise-induced myokines and Langberg H & Kristiansen J (2005) Increase in
their role in chronic diseases. Brain Behav Immun 25, interstitial interleukin-6 of human skeletal muscle with
811–816. repetitive low-force exercise. J Appl Physiol 98,
65 Pedersen BK (2009) The diseasome of physical 477–481.
inactivity – and the role of myokines in muscle – fat 77 Steensberg A, Van Hall G, Osada T, Sacchetti M,
cross talk. J Physiol 587, 5559–5568. Saltin B & Pedersen KB (2000) Production of
66 Fischer CP (2006) Interleukin-6 in acute exercise and interleukin-6 in contracting human skeletal muscles
training: what is the biological relevance? Exerc can account for the exercise-induced increase in
Immunol Rev 12, 6–33. plasma interleukin-6. J Physiol 529, 237–242.
67 Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, 78 De Rossi M, Bernasconi P, Baggi F, de Waal Malefyt
Henson DA, Utter A, Davis JM, Williams F & R & Mantegazza R (2000) Cytokines and chemokines

4144 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
 ~oz-C
P. Mun anoves et al. IL-6 myokine signaling in skeletal muscle

are both expressed by human myoblasts: possible lipolysis and fat oxidation in humans. J Clin
relevance for the immune pathogenesis of muscle Endocrinol Metab 88, 3005–3010.
inflammation. Int Immunol 12, 1329–1335. 90 Steensberg A, Fischer CP, Sacchetti M, Keller C,
79 Bartoccioni E, Michaelis D & Hohlfeld R (1994) Osada T, Schjerling P, Van Hall G, Febbraio MA &
Constitutive and cytokine-induced production of Pedersen BK (2003) Acute interleukin-6 administration
interleukin-6 by human myoblasts. Immunol Lett 42, does not impair muscle glucose uptake or whole-body
135–138. glucose disposal in healthy humans. J Physiol 548,
80 Keller C, Hellsten Y, Steensberg A & Pedersen BK 631–638.
(2006) Differential regulation of IL-6 and TNF-alpha 91 Carey AL, Steinberg GR, Macaulay SL, Thomas WG,
via calcineurin in human skeletal muscle cells. Holmes AG, Ramm G, Prelovsek O, Hohnen-Behrens
Cytokine 36, 141–147. C, Watt MJ, James DE et al. (2006) Interleukin-6
81 Haugen F, Norheim F, Lian H, Wensaas AJ, Dueland increases insulin-stimulated glucose disposal in humans
S, Berg O, Funderud A, Skalhegg BS, Raastad T & and glucose uptake and fatty acid oxidation in vitro
Drevon CA (2010) IL-7 is expressed and secreted by via AMP-activated protein kinase. Diabetes 55, 2688–
human skeletal muscle cells. Am J Physiol Cell Physiol 2697.
298, C807–C816. 92 Febbraio MA, Hiscock N, Sacchetti M, Fischer CP &
82 Green CJ, Pedersen M, Pedersen BK & Scheele C Pedersen BK (2004) Interleukin-6 is a novel factor
(2011) Elevated NF-kappaB activation is conserved in mediating glucose homeostasis during skeletal muscle
human myocytes cultured from obese type 2 diabetic contraction. Diabetes 53, 1643–1648.
patients and attenuated by AMP-activated protein 93 Al-Khalili L, Bouzakri K, Glund S, Lonnqvist F,
kinase. Diabetes 60, 2810–2819. Koistinen HA & Krook A (2006) Signaling specificity
83 Whitham M, Chan MH, Pal M, Matthews VB, of interleukin-6 action on glucose and lipid
Prelovsek O, Lunke S, El-Osta A, Broenneke H, Alber metabolism in skeletal muscle. Mol Endocrinol 20,
J, Bruning JC et al. (2012) Contraction-induced 3364–3375.
interleukin-6 gene transcription in skeletal muscle is 94 Kelly M, Gauthier MS, Saha AK & Ruderman NB
regulated by c-Jun terminal kinase/activator protein-1. (2009) Activation of AMP-activated protein kinase by
J Biol Chem 287, 10771–10779. interleukin-6 in rat skeletal muscle: association with
84 Lambernd S, Taube A, Schober A, Platzbecker B, changes in cAMP, energy state, and endogenous fuel
Gorgens SW, Schlich R, Jeruschke K, Weiss J, mobilization. Diabetes 58, 1953–1960.
Eckardt K & Eckel J (2012) Contractile activity of 95 Sadagurski M, Norquay L, Farhang J, D’Aquino
human skeletal muscle cells prevents insulin resistance K, Copps K & White MF (2010) Human IL6
by inhibiting pro-inflammatory signalling pathways. enhances leptin action in mice. Diabetologia 53,
Diabetologia 55, 1128–1139. 525–535.
85 Pedersen BK (2012) Muscular interleukin-6 and its 96 Wunderlich FT, Strohle P, Konner AC, Gruber S,
role as an energy sensor. Med Sci Sports Exerc 44, Tovar S, Bronneke HS, Juntti-Berggren L, Li LS, Van
392–396. Rooijen N, Libert C et al. (2010) Interleukin-6
86 Ruderman NB, Keller C, Richard AM, Saha AK, signaling in liver-parenchymal cells suppresses hepatic
Luo Z, Xiang X, Giralt M, Ritov VB, Menshikova inflammation and improves systemic insulin action.
EV, Kelley DE et al. (2006) Interleukin-6 regulation Cell Metab 12, 237–249.
of AMP-activated protein kinase. Potential role in 97 Bouzakri K, Plomgaard P, Berney T, Donath MY,
the systemic response to exercise and prevention of Pedersen BK & Halban PA (2011) Bimodal effect on
the metabolic syndrome. Diabetes 55(Suppl 2), pancreatic beta-cells of secretory products from
S48–S54. normal or insulin-resistant human skeletal muscle.
87 Fischer CP, Plomgaard P, Hansen AK, Pilegaard H, Diabetes 60, 1111–1121.
Saltin B & Pedersen BK (2004) Endurance training 98 Ellingsgaard H, Hauselmann I, Schuler B, Habib AM,
reduces the contraction-induced interleukin-6 mRNA Baggio LL, Meier DT, Eppler E, Bouzakri K, Wueest
expression in human skeletal muscle. Am J Physiol S, Muller YD et al. (2011) Interleukin-6 enhances
Endocrinol Metab 287, E1189–E1194. insulin secretion by increasing glucagon-like peptide-1
88 Wolsk E, Mygind H, Grondahl TS, Pedersen BK & secretion from L cells and alpha cells. Nat Med 17,
Van Hall G (2010) IL-6 selectively stimulates fat 1481–1489.
metabolism in human skeletal muscle. Am J Physiol 99 Tisdale MJ (2009) Mechanisms of cancer cachexia.
Endocrinol Metab 299, E832–E840. Physiol Rev 89, 381–410.
89 Van Hall G, Steensberg A, Sacchetti M, Fischer C, 100 Carson JA & Baltgalvis KA (2010) Interleukin-6 as a
Keller C, Schjerling P, Hiscock N, Moller K, Saltin B, key regulator of muscle mass during cachexia. Exerc
Febbraio MA et al. (2003) Interleukin-6 stimulates Sport Sci Rev 38, 168–176.

FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS 4145
IL-6 myokine signaling in skeletal muscle ~oz-C
P. Mun anoves et al.

101 Tsoli M & Robertson G (2013) Cancer cachexia: Monden M (1996) Anti-interleukin-6 receptor
malignant inflammation, tumorkines, and metabolic antibody prevents muscle atrophy in colon-26
mayhem. Trends Endocrinol Metab 24, 174–183. adenocarcinoma-bearing mice with modulation of
102 Fearon KC, Glass DJ & Guttridge DC (2012) Cancer lysosomal and ATP-ubiquitin-dependent proteolytic
cachexia: mediators, signaling, and metabolic pathways. Int J Cancer 68, 637–643.
pathways. Cell Metab 16, 153–166. 114 Soda K, Kawakami M, Kashii A & Miyata M (1994)
103 Strassmann G, Fong M, Kenney JS & Jacob CO Characterization of mice bearing subclones of
(1992) Evidence for the involvement of interleukin 6 in colon 26 adenocarcinoma disqualifies interleukin-6 as
experimental cancer cachexia. J Clin Invest 89, 1681– the sole inducer of cachexia. Jpn J Cancer Res 85,
1684. 1124–1130.
104 Oldenburg HS, Rogy MA, Lazarus DD, Van Zee KJ, 115 Soda K, Kawakami M, Kashii A & Miyata M (1995)
Keeler BP, Chizzonite RA, Lowry SF & Moldawer Manifestations of cancer cachexia induced by colon 26
LL (1993) Cachexia and the acute-phase protein adenocarcinoma are not fully ascribable to interleukin-
response in inflammation are regulated by interleukin- 6. Int J Cancer 62, 332–336.
6. Eur J Immunol 23, 1889–1894. 116 Haddad F, Zaldivar F, Cooper DM & Adams GR
105 Garcia-Martinez C, Lopez-Soriano FJ & Argiles JM (2005) IL-6-induced skeletal muscle atrophy. J Appl
(1994) Interleukin-6 does not activate protein Physiol 98, 911–917.
breakdown in rat skeletal muscle. Cancer Lett 76, 1–4. 117 Janssen SP, Gayan-Ramirez G, Van den Bergh A,
106 Goodman MN (1994) Interleukin-6 induces skeletal Herijgers P, Maes K, Verbeken E & Decramer M
muscle protein breakdown in rats. Proc Soc Exp Biol (2005) Interleukin-6 causes myocardial failure and
Med 205, 182–185. skeletal muscle atrophy in rats. Circulation 111, 996–
107 Williams A, Wang JJ, Wang L, Sun X, Fischer JE & 1005.
Hasselgren PO (1998) Sepsis in mice stimulates muscle 118 Bodell PW, Kodesh E, Haddad F, Zaldivar FP,
proteolysis in the absence of IL-6. Am J Physiol 275, Cooper DM & Adams GR (2009) Skeletal muscle
R1983–R1991. growth in young rats is inhibited by chronic
108 Ebisui C, Tsujinaka T, Morimoto T, Kan K, Iijima S, exposure to IL-6 but preserved by concurrent
Yano M, Kominami E, Tanaka K & Monden M (1995) voluntary endurance exercise. J Appl Physiol 106,
Interleukin-6 induces proteolysis by activating 443–453.
intracellular proteases (cathepsins B and L, proteasome) 119 Steensberg A, Febbraio MA, Osada T, Schjerling P,
in C2C12 myotubes. Clin Sci (Lond) 89, 431–439. Van Hall G, Saltin B & Pedersen BK (2001)
109 Espat NJ, Auffenberg T, Rosenberg JJ, Rogy M, Interleukin-6 production in contracting human skeletal
Martin D, Fang CH, Hasselgren PO, Copeland EM & muscle is influenced by pre-exercise muscle glycogen
Moldawer LL (1996) Ciliary neurotrophic factor is content. J Physiol 537, 633–639.
catabolic and shares with IL-6 the capacity to induce 120 Van Hall G, Steensberg A, Fischer C, Keller C,
an acute phase response. Am J Physiol 271, R185– Moller K, Moseley P & Pedersen BK (2008)
R190. Interleukin-6 markedly decreases skeletal muscle
110 Llovera M, Carbo N, Lopez-Soriano J, Garcia- protein turnover and increases nonmuscle amino acid
Martinez C, Busquets S, Alvarez B, Agell N, Costelli utilization in healthy individuals. J Clin Endocrinol
P, Lopez-Soriano FJ, Celada A et al. (1998) Different Metab 93, 2851–2858.
cytokines modulate ubiquitin gene expression in rat 121 Raj DS, Moseley P, Dominic EA, Onime A,
skeletal muscle. Cancer Lett 133, 83–87. Tzamaloukas AH, Boyd A, Shah VO, Glew R, Wolfe
111 Tsujinaka T, Ebisui C, Fujita J, Kishibuchi M, R & Ferrando A (2008) Interleukin-6 modulates
Morimoto T, Ogawa A, Katsume A, Ohsugi Y, hepatic and muscle protein synthesis during
Kominami E & Monden M (1995) Muscle undergoes hemodialysis. Kidney Int 73, 1054–1061.
atrophy in association with increase of lysosomal 122 De Benedetti F, Alonzi T, Moretta A, Lazzaro D,
cathepsin activity in interleukin-6 transgenic mouse. Costa P, Poli V, Martini A, Ciliberto G & Fattori E
Biochem Biophys Res Commun 207, 168–174. (1997) Interleukin 6 causes growth impairment in
112 Tsujinaka T, Fujita J, Ebisui C, Yano M, Kominami transgenic mice through a decrease in insulin-like
E, Suzuki K, Tanaka K, Katsume A, Ohsugi Y, growth factor-I. A model for stunted growth in
Shiozaki H et al. (1996) Interleukin 6 receptor children with chronic inflammation. J Clin Invest 99,
antibody inhibits muscle atrophy and modulates 643–650.
proteolytic systems in interleukin 6 transgenic mice. J 123 Nemet D, Eliakim A, Zaldivar F & Cooper DM
Clin Invest 97, 244–249. (2006) Effect of rhIL-6 infusion on GH?IGF-I axis
113 Fujita J, Tsujinaka T, Yano M, Ebisui C, Saito H, mediators in humans. Am J Physiol Regul Integr Comp
Katsume A, Akamatsu K, Ohsugi Y, Shiozaki H & Physiol 291, R1663–R1668.

4146 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS
 ~oz-C
P. Mun anoves et al. IL-6 myokine signaling in skeletal muscle

124 De Benedetti F, Pignatti P, Vivarelli M, Meazza C, cells maintaining proper regulation of protein
Ciliberto G, Savino R & Martini A (2001) In vivo turnover. Am J Physiol Cell Physiol 293, C712–C722.
neutralization of human IL-6 (hIL-6) achieved by 136 Li YP, Chen Y, John J, Moylan J, Jin B, Mann DL &
immunization of hIL-6-transgenic mice with a hIL-6 Reid MB (2005) TNF-alpha acts via p38 MAPK to
receptor antagonist. J Immunol 166, 4334–4340. stimulate expression of the ubiquitin ligase atrogin1/
125 Firth SM & Baxter RC (2002) Cellular actions of the MAFbx in skeletal muscle. FASEB J 19, 362–370.
insulin-like growth factor binding proteins. Endocrinol 137 Zhang G & Li YP (2012) p38beta MAPK upregulates
Rev 23, 824–854. atrogin1/MAFbx by specific phosphorylation of
126 De Benedetti F, Meazza C, Oliveri M, Pignatti P, C/EBPbeta. Skeletal Muscle 2, 20.
Vivarelli M, Alonzi T, Fattori E, Garrone S, Barreca 138 Zhang L, Du J, Hu Z, Han G, Delafontaine P, Garcia
A & Martini A (2001) Effect of IL-6 on IGF binding G & Mitch WE (2009) IL-6 and serum amyloid A
protein-3: a study in IL-6 transgenic mice and in synergy mediates angiotensin II-induced muscle
patients with systemic juvenile idiopathic arthritis. wasting. J Am Soc Nephrol 20, 604–612.
Endocrinology 142, 4818–4826. 139 Sun DF, Zheng Z, Tummala P, Oh J, Schaefer F &
127 Dall R, Lange KH, Kjaer M, Jorgensen JO, Rabkin R (2004) Chronic uremia attenuates growth
Christiansen JS, Orskov H & Flyvbjerg A (2001) No hormone-induced signal transduction in skeletal
evidence of insulin-like growth factor-binding muscle. J Am Soc Nephrol 15, 2630–2636.
protein 3 proteolysis during a maximal exercise test in 140 Spangenburg EE, Brown DA, Johnson MS & Moore
elite athletes. J Clin Endocrinol Metab 86, 669–674. RL (2006) Exercise increases SOCS-3 expression in rat
128 Pihl S, Carlsson-Skwirut C, Berg U, Ekstrom K & skeletal muscle: potential relationship to IL-6
Bang P (2006) Acute interleukin-6 infusion increases expression. J Physiol 572, 839–848.
IGFBP-1 but has no short-term effect on IGFBP-3 141 Giger JM, Bodell PW, Zeng M, Baldwin KM &
proteolysis in healthy men. Horm Res 65, 177–184. Haddad F (2009) Rapid muscle atrophy response to
129 Nystrom G, Pruznak A, Huber D, Frost RA & Lang unloading: pretranslational processes involving MHC
CH (2009) Local insulin-like growth factor I prevents and actin. J Appl Physiol 107, 1204–1212.
sepsis-induced muscle atrophy. Metabolism 58, 787– 142 Bonetto A, Aydogdu T, Kunzevitzky N, Guttridge
797. DC, Khuri S, Koniaris LG & Zimmers TA (2011)
130 Braun TP, Zhu X, Szumowski M, Scott GD, STAT3 activation in skeletal muscle links muscle
Grossberg AJ, Levasseur PR, Graham K, Khan S, wasting and the acute phase response in cancer
Damaraju S, Colmers WF et al. (2011) Central cachexia. PLoS ONE 6, e22538.
nervous system inflammation induces muscle atrophy 143 Bonetto A, Aydogdu T, Jin X, Zhang Z, Zhan R,
via activation of the hypothalamic-pituitary-adrenal Puzis L, Koniaris LG & Zimmers TA (2012) JAK/
axis. J Exp Med 208, 2449–2463. STAT3 pathway inhibition blocks skeletal muscle
131 Lieskovska J, Guo D & Derman E (2003) Growth wasting downstream of IL-6 and in experimental
impairment in IL-6-overexpressing transgenic mice is cancer cachexia. Am J Physiol Endocrinol Metab 303,
associated with induction of SOCS3 mRNA. Growth E410–E421.
Horm IGF Res 13, 26–35. 144 Yamada E, Bastie CC, Koga H, Wang Y, Cuervo AM
132 Franckhauser S, Elias I, Rotter Sopasakis V, Ferre & Pessin JE (2012) Mouse skeletal muscle fiber-type-
T, Nagaev I, Andersson CX, Agudo J, Ruberte J, specific macroautophagy and muscle wasting are
Bosch F & Smith U (2008) Overexpression of Il6 regulated by a Fyn/STAT3/Vps34 signaling pathway.
leads to hyperinsulinaemia, liver inflammation and Cell Rep 1, 557–569.
reduced body weight in mice. Diabetologia 51, 145 Masiero E, Agatea L, Mammucari C, Blaauw B, Loro
1306–1316. E, Komatsu M, Metzger D, Reggiani C, Schiaffino S
133 Haddad F & Adams GR (2006) Aging-sensitive & Sandri M (2009) Autophagy is required to maintain
cellular and molecular mechanisms associated with muscle mass. Cell Metab 10, 507–515.
skeletal muscle hypertrophy. J Appl Physiol 100, 146 Song YH, Li Y, Du J, Mitch WE, Rosenthal N &
1188–1203. Delafontaine P (2005) Muscle-specific expression of
134 Morris RT, Spangenburg EE & Booth FW (2004) IGF-1 blocks angiotensin II-induced skeletal muscle
Responsiveness of cell signaling pathways during the wasting. J Clin Invest 115, 451–458.
failed 15-day regrowth of aged skeletal muscle. J Appl 147 Yoshida T, Semprun-Prieto L, Sukhanov S &
Physiol 96, 398–404. Delafontaine P (2010) IGF-1 prevents ANG II-
135 Mieulet V, Roceri M, Espeillac C, Sotiropoulos A, induced skeletal muscle atrophy via Akt- and Foxo-
Ohanna M, Oorschot V, Klumperman J, Sandri M & dependent inhibition of the ubiquitin ligase atrogin-1
Pende M (2007) S6 kinase inactivation impairs growth expression. Am J Physiol Heart Circ Physiol 298,
and translational target phosphorylation in muscle H1565–H1570.

FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS 4147
IL-6 myokine signaling in skeletal muscle ~oz-C
P. Mun anoves et al.

148 Rui L, Yuan M, Frantz D, Shoelson S & White MF muscle cells: role of IL-6 mRNA stabilization and
(2002) SOCS-1 and SOCS-3 block insulin signaling by Ca2+-dependent mechanisms. Am J Physiol Cell
ubiquitin-mediated degradation of IRS1 and IRS2. J Physiol 293, C1139–C1147.
Biol Chem 277, 42394–42398. 151 Ji LL, Gomez-Cabrera MC, Steinhafel N & Vina J
149 Keller P, Keller C, Carey AL, Jauffred S, Fischer CP, (2004) Acute exercise activates nuclear factor (NF)-
Steensberg A & Pedersen BK (2003) Interleukin-6 kappaB signaling pathway in rat skeletal muscle.
production by contracting human skeletal muscle: FASEB J 18, 1499–1506.
autocrine regulation by IL-6. Biochem Biophys Res 152 Vella L, Caldow MK, Larsen AE, Tassoni D, Della
Commun 310, 550–554. Gatta PA, Gran P, Russell AP & Cameron-Smith D
150 Weigert C, Dufer M, Simon P, Debre E, Runge H, (2012) Resistance exercise increases NF-kappaB
Brodbeck K, Haring HU & Schleicher ED (2007) activity in human skeletal muscle. Am J Physiol Regul
Upregulation of IL-6 mRNA by IL-6 in skeletal Integr Comp Physiol 302, R667–R673.

4148 FEBS Journal 280 (2013) 4131–4148 ª 2013 The Authors. FEBS Journal published by John Wiley & Sons Ltd on behalf of FEBS