8 • Exercise-induced cytokine responses

cytokine expression and secretion by skeletal muscle cells:
regulatory mechanisms and exercise effects
Jonathan M. Peake1, Paul Della gatta2, Katsuhiko suzuki3, David c. nieman4

School of Biomedical Sciences and Institute of Health and Biomedical Sciences, Queensland University of Technology,
Brisbane, Australia
2 Centre for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University,
Melbourne, Australia
3 Faculty of Sport Sciences, Waseda University, Cooperative Major in Advanced Health Science,
Tokyo University of Agriculture and Technology/Waseda University, Tokorozawa, Saitama, Japan
4 Human Performance Laboratory, Appalachian State University, North Carolina Research Campus,
Kannapolis, North Carolina, USA

1

aBstRact

Cytokines are important mediators of various aspects ofhealth and disease, including appetite, glucose and lipid
metabolism, insulin sensitivity, skeletal muscle hypertrophy
and atrophy. Over the past decade or so, considerable attention has focused on the potential for regular exercise to counteract a range of disease states by modulating cytokine production. Exercise stimulates moderate to large increases in
the circulating concentrations of interleukin (IL)-6, IL-8, IL10, IL-1 receptor antagonist, granulocyte-colony stimulating
factor, and smaller increases in tumor necrosis factor-α,monocyte chemotactic protein-1, IL-1β, brain-derived neurotrophic factor, IL-12p35/p40 and IL-15. Although many ofthese cytokines are also expressed in skeletal muscle, not all
are released from skeletal muscle into the circulation during
exercise. Conversely, some cytokines that are present in thecirculation are not expressed in skeletal muscle after exercise.
The reasons for these discrepant cytokine responses to exercise are unclear. In this review, we address these uncertainties
by summarizing the capacity of skeletal muscle cells to produce cytokines, analyzing other potential cellular sources ofcirculating cytokines during exercise, and discussing the soluble factors and intracellular signaling pathways that regulate
cytokine synthesis (e.g., RNA-binding proteins, microRNAs,
suppressor of cytokine signaling proteins, soluble receptors).

intRODUctiOn

Cytokines comprise a large family of polypeptides or proteins. This family includes interleukins, interferons, growthand colony-stimulating factors, chemokines, members of thetumor necrosis factor group and transforming growth factors.
Cytokines play an integrative and regulatory role as universal
intercellular messengers. Once secreted, they can mediate
intercellular communication locally or systemically. Alternatively, they can mediate intercellular contact even whenbound to cell membranes (200). These characteristics distinguish cytokines from other intercellular messengers such asContact details:
Jonathan Peake, Institute of Health and Biomedical Innovation,
Queensland University of Technology, Brisbane, QLD 4059, Australia
Ph: +61 7 3138 6140, Email: jonathan.peake@qut.edu.au
EIR 21 2015

adhesion molecules, which require direct cell-to-cell contact,and hormones, which are produced by specialized endocrineorgans and circulate throughout the body to exert theiractions. Most cytokines are inducible mediators, are transported through the systemic circulation and are synthesized rapidly by multiple cell types in response to various stimuli. Individual cell types can express and secrete several cytokines
simultaneously in response to a single stimulus (200).
Cytokines are pleiotropic because they influence several cell
types, and elicit different effects, depending on the type of target cells. They exert their pleiotropic actions in two phases.
First, they bind to specific receptors expressed on cells withdifferent origins and/or functions. Second, they mediate signaltransduction through various intracellular messengers andtranscription factors. The biological effects of cytokines
depend on the presence and concentrations of other cytokines
with synergistic, additive or counter-regulatory actions (200).
Cytokines can act in an autocrine, paracrine or endocrine
fashion to induce or suppress their own synthesis and regulate
the production of other cytokines and their receptors. They
possess an important characteristic of self-limiting synthesis
through various auto-regulatory mechanisms (e.g., RNAinstability) and negative feedback pathways. These pathways
include synthesis of eicosanoids and corticosteroid hormones,
expression of soluble receptors, and induction of intracellulartranscription factors that block signal transduction (200).

The main function of cytokines is to regulate immune function. However, their wide-ranging effects on cell proliferation,differentiation, migration, survival and apoptosis allow themto play a role in homeostatic control of various tissues, organs
and systems. For example, together with hormones and neuropeptides, cytokines mediate interactions between the nervous, endocrine and immune systems. Some cytokines also
control body temperature, fatigue, appetite and metabolism. A
link between cytokines and skeletal muscle was first established almost 50 years ago when researchers identified that an
endogenous pyrogen was present in skeletal muscle (203).
Cannon and Kluger (32) subsequently made another important discovery that endurance exercise induces the systemic
release of a pyrogenic compound. These findings have since
stimulated considerable interest in the biological significanceand regulation of cytokine production in muscle during exercise and as a result of sepsis, aging, cancer cachexia andchronic inflammatory diseases.

Exercise-induced cytokine responses • 9
Initially, exercise research focused on the role of cytokines inmediating inflammatory responses to exercise-induced muscle damage. Evidence has accumulated over the past decadethat cytokines play a much broader role during exercise. We
now know that cytokines act in a hormone-like manner during
exercise, mediating metabolism in working skeletal muscle,
the liver and adipose tissue, angiogenesis and neurobiology(166). Following exercise, there is an increase in the circulating concentrations of assorted cytokines. Gene expression forsome of these cytokines also increases within skeletal muscle.
However, there appears to be a dissociation between local
gene expression in skeletal muscle and the systemic concentration of other cytokines. For example, after exercise, tumor
necrosis factor (TNF)-α and interleukin (IL)-1β expression inskeletal muscle increases, but the circulating concentration ofthese cytokines does not change (or only increases slightly).
Conversely, the circulating concentrations of IL-1 receptor
antagonist (IL-1ra) and IL-10 increase markedly, but thesecytokines are not expressed in skeletal muscle after exercise.

Several excellent reviews have discussed the evidence thatskeletal muscle is a secretory organ (167, 168, 183, 232). Yet
relatively few studies have specifically examined whether
skeletal muscle cells themselves are the main source ofcytokine gene expression in skeletal muscle during exercise.
In this review, we examine this notion in more detail by (1)reviewing the findings from studies of cytokine expression
and secretion in cultured skeletal muscle cells, and (2) summarizing the results of studies that have used histologicalstaining of cytokine expression in cross-sections of muscle
tissue. We also discuss other potential sources of cytokines

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both in skeletal muscle, other tissues and the systemic circulation. Most research to date has investigated the systemic factors and intracellular signaling pathways that stimulate
cytokine secretion by skeletal muscle cells. By contrast, muchless is known about the factors that restrict or inhibit cytokine
translation in skeletal muscle cells, and cytokine release into
the circulation during exercise. We propose some potential
negative regulatory mechanisms that may govern cytokine
expression and secretion by skeletal muscle cells. Considering
the important role of cytokines as local and systemic mediators of various aspects of health and disease, we contend that
continuing research is needed to determine the dominantsources and regulation of cytokine production in the body.

lOcal anD systeMic cytOKine
ResPOnses tO exeRcise

Numerous studies have investigated changes in the circulating
concentrations of cytokines following exercise. Cytokine
responses are generally dependent on the combination ofmode, intensity, and duration of exercise. In the case of IL-6,
prolonged running produces the greatest increase in plasmaIL-6 concentration (167, 184). Indeed, circulating IL-6 canincrease up to 120× following endurance exercise. IL-1ra (upto 90×), IL-10 (up to 80×), IL-8 (15×) and monocyte chemotactic protein (MCP-1) (up to 3×) also consistently increase in
the circulation following exercise (39, 64, 68, 102, 151-154,
164, 165, 208, 212, 219, 225) (Table 1). There is substantial
individual variability in the magnitude of changes in thesecytokines in plasma after exercise (Figure 1).

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Figure 1. Individual variability in plasma cytokine responses to the Western States 160 km Endurance Run. Data indicate the change (in pg/ml)
from pre- to post-exercise. Data are combined from Int J Sports Med 24:541-547, 2003; Brain Beh Immun 19:398-403, 2005; Brain Beh Immun
20:578–584, 2006.

EIR 21 2015

10 • Exercise-induced cytokine responses

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Some of this variability appears to be related to variation in
exercise intensity (156) and the extent of exercise-induced
muscle damage (157, 228). By contrast, the plasma/serum
concentrations of TNF-α (4×), brain-derived neurotrophic factor (BDNF) (2.5×), IL-1β (2×), IL-12p40 (0.3×), IL-15(0.05×) increase to a smaller extent, whereas leukemia
inhibitory factor (LIF) and transforming growth factor (TGF)β remain unchanged following exercise (25, 29, 39, 137, 153,
154, 186, 190, 220, 225).

The gene expression of IL-1β, IL-6, IL-8, IL-10, IL-15, TNF-α,
MCP-1, LIF and TGF-β in skeletal muscle increases following
endurance exercise (39, 64, 68, 82, 102, 124, 147, 151, 152,
154, 208, 212) and resistance exercise (25, 50, 94, 124, 149,
150, 192) (Table 1). BDNF mRNA expression also tends toincrease (non-significantly) in response to endurance exercise(137). Similar to plasma cytokine responses, exercise-inducedchanges in cytokine gene expression in muscle can also behighly variable, possibly due to variation in single nucleotide
polymorphisms within cytokine genes (52, 186). However, lessis known about changes in the protein abundance of thesecytokines in skeletal muscle after exercise. IL-6 and BDNF
protein expression increases in working skeletal muscle following endurance exercise (68, 89, 137), while the protein abundance of IL-6, IL-8 and MCP-1 also increases after resistance
exercise (50, 51) and eccentric exercise (94). Changes in IL-1β
EIR 21 2015

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are inconsistent (66, 129, 130), whereas IL-15 and LIF protein
content does not change following exercise (25, 26, 130, 149).

In contrast with pro-inflammatory cytokines, exercise-inducedchanges in the anti-inflammatory cytokines IL-4 and IL-13 areless well characterized. We recently reported that IL-4 protein
expression in muscle tended to decrease 2 h after resistance
exercise in young men. However, following 12 weeks ofresistance training, IL-4 protein expression increased when thesame individuals performed another bout of resistance exercise (51). This finding suggests that IL-4 may play a role inmuscular adaptations to training. In the same study, weobserved that IL-13 protein expression in muscle did notchange significantly after either bout of exercise (51).

cytOKine exPRessiOn anD secRetiOn
By sKeletal MUscle cells

Most of the evidence for cytokine expression in skeletal muscle is derived from the analysis of isolated RNA or protein
extracts from homogenized muscle. However, muscle
homogenates reflect contributions from intracellular,
sequestered and interstitial sources of cytokines (23). This
makes it difficult to identify specific cellular sources ofcytokines in vivo. An extensive body of research has exploredExercise-induced cytokine responses • 11
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the capacity of skeletal muscle cells to produce cytokines invitro by culturing skeletal muscle cells with various agents,
and by subjecting skeletal muscle cells to cyclic strain andelectromagnetic pulse stimulation (Table 2).

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Evidence from cell culture studies
C2C12 myoblasts, L6 muscle cells and human myoblasts constitutively express IL-8 (47, 133), IL-12 (72), IL-15 (180) and
TGF-β (72). Some, but not all studies report that myoblasts
EIR 21 2015

12 • Exercise-induced cytokine responses
also constitutively express IL-1β, IL-1ra, IL-6, TNF-α andMCP-1 (17, 47, 70-73, 106, 133, 144). Myoblasts do not
express IL-10 or interferon (IFN)-γ (144). The constitutive
expression of cytokines is generally stronger in differentiatedmyotubes compared with myoblasts (83, 85, 86, 102, 107,
134, 144, 235) (Table 2).

Myoblasts and myotubes express and secrete cytokines invitro in response to a wide range of stimuli (Table 2). ATP,
H2O2, xanthine/xanthine oxidase, nitric oxide and epinephrine
are produced during exercise through redox reactions andautonomic nervous activity. These agents directly regulate thesynthesis of cytokines by skeletal muscle cells by activating
various signaling pathways (6, 70-72, 96, 107, 128, 235). The
regulatory influence of TNF-α, IL-1β, IL-6, IFN-γ, TGF-β and
HSP60 is probably less direct, and depends on their relative
concentration within the local microenvironment of skeletal
muscle. Many of the agents listed above induce a concentration-dependent increase in the secretion of IL-6, IL-8, TNF-αand MCP-1 (70, 72, 73, 85, 107, 134, 144). LPS, TNF-α, IL1β, IL-6, IFN-γ and epinephrine also induce a time-dependent
increase in the secretion of IL-6, TNF-α, TGF-β and MCP-1
for up to 48 hours (70-73, 133, 144). Human myotubes that
undergo cyclic mechanical strain release IL-6, IL-8, MCP-1
and G-CSF (172). Mouse (62, 146, 235), rat (31) and human(25, 182, 195) myotubes that contract in response to electromagnetic pulse stimulation release a wide array of cytokines(Table 2). In addition to well characterized cytokines, the listof ‘contraction-responsive’ cytokines continues to grow (182,
195).

The findings from cell culture studies provide important information on skeletal muscle cell secretion of cytokines in thecontext of trauma, sepsis or chronic inflammatory conditions.
However, these findings are not necessarily applicable tounderstanding how skeletal muscle cells generate cytokines
during exercise, for several reasons. The concentrations ofmost of the agents are most likely lower in skeletal muscle
during exercise compared with the concentrations used in cell
culture studies. The period for which skeletal muscle is
exposed to these agents during exercise is also typically shorter than the incubation periods used in cell culture studies.
Although epinephrine stimulates IL-6 mRNA expression andsecretion (70), epinephrine appears to play a relatively minor
role in regulating systemic changes in IL-6 during exercise(214). Last, cyclic strain and electromagnetic pulse stimulation of myotubes do not fully reflect the dynamic conditionsin skeletal muscle during exercise, where both stimulatory
and inhibitory agents are present.

Evidence from in vivo muscle analysis
Human biopsy studies reveal that skeletal muscle expresses
mRNA for numerous cytokines (Table 1) (25, 29, 83, 91, 94,
109, 149, 152, 154, 212). Mature myofibers make up most of
the cellular mass within skeletal muscle, and as described in
the previous section, myotubes express mRNA for various
cytokines. Nevertheless, muscle homogenates represent a
mixture of different types of cells; other inflammatory andstromal cells in skeletal muscle also secrete cytokines. Some
research has used immunohistochemistry and immunofluorescence staining to examine the cellular sources of cytokines in
EIR 21 2015

healthy human muscle at rest (68, 89, 149, 175). Malm et al.
(129) found that IL-6 and IL-1β are localized to both muscle
and non-muscle cells. The same group subsequently reported
that IL-6 expression is low within skeletal muscle cells themselves, whereas it is expressed in the epimysium (130). In
muscle of patients with inflammatory myopathies, cytokines
are highly abundant, but are mainly localized to other cell
types such as inflammatory T cells and macrophages, and inproximity to blood vessels in the endomysium and perimysium (46, 194). Collectively, these findings demonstrate thatcytokines are likely secreted by various cell types present inskeletal muscle, and not exclusively by skeletal muscle cells
themselves.

Surprisingly little research has used RNA in situ hybridization, immunohistochemistry or immunofluorescence staining
to identify which fibers and resident cell types (e.g., endothelial cells, infiltrating leucocytes, satellite cells) in skeletal
muscle produce cytokines in response to exercise. Table 3
summarizes the results of studies that have attempted to identify where cytokines are expressed in skeletal muscle after
exercise or muscle contractions. Hiscock et al. (89) report that
following endurance exercise, both IL-6 mRNA and protein
are expressed mainly in type II fibers with high muscle glycogen content. They propose that the greater IL-6 expression in
type II fibers may result from greater release of Ca2+ from thesarcoplasmic reticulum into the cytosol of the type II fibers(89). Following eccentric exercise, Hubal et al. (94) observedthat MCP-1 is mainly expressed within the interstitial space
between myofibers, and localizes with macrophages andPax7+ satellite cells. Two studies have demonstrated that IL-6also localizes with Pax7+ satellite cells in the basal lamina ofmuscle fibers after eccentric exercise (138) and compensatedhypertrophy (197). Following downhill running, Malm et al.
(130) reported that IL-1β is mainly localized to non-muscle
cells, whereas Fielding et al. (66) found that IL-1β is localized
to the pericellular space. Using immunofluorescence staining
for MCP-1 and IL-8, we recently reported that thesechemokines are not present within mature myofibers after
exercise. Rather, they are localized within the endomysium
between muscle fibers and in close proximity to a number ofcell types including macrophages, satellite cells and bloodvessels (50). Hoier et al (90) investigated the subcellular
localization of VEGF in muscle 2 h after cycling. They discovered that VEGF was located in the subsarcolemmal
regions, between the contractile elements within the muscle
fibers, and in pericytes positioned on the skeletal muscle capillaries. Lauritzen et al (116) conducted an elegant study inwhich they incorporated an enhanced green fluorescent protein tagged for IL-6 into muscle fibers isolated from thequadriceps muscles of mice. At rest, the fluorescent tag was
localized in vesicular structures at the surface and in the interior of the transfected muscle fiber. Following in situ contractions of the fibers, the number of vesicles expressing the fluorescent tag decreased in both locations, indicating vesiculartransport of IL-6 out of the fiber. These diverse findings highlight the need for more research to gain a better understandingof the local regulation and secretion of cytokines in muscle
during exercise.

Exercise-induced cytokine responses • 13

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DissOciatiOn Between lOcal anD
systeMic cytOKine ResPOnsestO exeRcise

Curiously, although many cytokines are expressed in skeletal
muscle following exercise, with the exception of IL-6, they
are not released into the circulation—at least in large amounts(65, 68, 211, 212). In explanation of these observations, it has
been suggested that some cytokines are produced locally byinterstitial cells, and may not enter the circulation (130, 191).
Catoire et al (37) recently conducted a systematic comparisonof cytokine gene expression in muscle and plasma cytokine
concentrations after one-legged 1 h cycling at 60% heart rate
reserve. They discovered that mRNA expression of IL-6,
MCP-1, CXCL2 (macrophage inflammatory protein-2α) and
CX3CL1 (fractalkine) was significantly upregulated. By contrast, mRNA expression of other cytokines including IL-7, IL8, IL-15 and BDNF did not change significantly after exercise. Within plasma, MCP-1 and fractalkine increased after
exercise, whereas IL-6 remained unchanged. This is the only
study to report simultaneous changes in MCP-1 andfractalkine within muscle and plasma following exercise. The
finding that plasma IL-6 concentration did not change despite
local expression in muscle may reflect the relatively small
muscle mass and low intensity of exercise (37). An alternative
explanation for the dissociation between local and systemic
cytokine responses is that skeletal muscle may not secrete sufficient quantities of cytokines to increase their concentrationin the systemic circulation.

Although distinct from exercise, Borge et al. (23) conducted
an elegant study to investigate whether cytokines are released
systemically from skeletal muscle in response to lipopolysaccharide (LPS). Plasma and interstitial fluid were collectedfrom mice 0.5, 1.5 and 3 h after intravenous administration of
3.5 mg/kg LPS. The concentrations and kinetics of changes incytokines were markedly different between interstitial fluid
and plasma. The findings from this study by Borge et al. (23)provide important information about skeletal muscle as asource of circulating cytokines. The higher concentration of
IL-1β in interstitial fluid compared with plasma suggests that
although skeletal muscle cells produce IL-1β, the systemic
release of IL-1β from skeletal muscle is probably tightly regulated. The higher concentrations of TNF-α, IL-10, MCP-1 inplasma compared with interstitial fluid 1.5 h after LPS infusion suggests that skeletal muscle is not a major source of
these cytokines in the circulation. The smaller difference inthe concentrations of IL-6 in plasma and interstitial fluid isconsistent with other evidence that skeletal muscle releases
IL-6 into the circulation during exercise (68, 211, 212). The
time course of changes in the secretion of cytokines in thisstudy is similar to that reported in plasma following exercise(160). The early secretion of TNF-α and IL-1β probably stimulated the sustained production of IL-6 (44, 71, 72, 125, 162).
Constitutive expression of IL-10 in skeletal muscle cells is
low (144), but IL-10 production may have increased in
response to the early rise in TNF-α and IL-1β secretion (67).

EIR 21 2015

14 • Exercise-induced cytokine responses

OtheR sOURces OF lOcal anD
systeMic cytOKines
DURing exeRcise

unchanged after exercise (1, 20, 154, 161). Monocyte intracellular cytokine production of IL-1β, IL-6, TNF-α, BDNF
increases, decreases or remains unchanged following exercise(27, 185, 207, 209, 210). Extracellular cytokine secretion bymononuclear cells or in whole blood stimulated with LPS is
also variable (1, 18, 19, 56, 57, 81, 87, 112, 173, 189, 202,
231). Fewer studies have investigated changes in cytokine
expression or secretion by T lymphocytes following exercise.
Two studies have reported that the number of IFN-γ+ T cells
decreases after exercise, while the number of IL-4+ T cells
remains unchanged (113, 213). In contrast with these findings,
Zaldivar et al (239) found that the percentage of T cells that
expressed IL-4, IL-6 and TNF-α increased following exercise.
Kakanis et al (99) also observed that the secretion of both Th1
cytokines (IL-2 and TNF-α) and Th2 cytokines (IL-6, IL-10)
by T cells stimulated with phytohemagglutinin increased after
exercise. Work by La Voy et al (117) demonstrated thatcytokine production during exercise may depend on changes
in the numbers certain subsets of T cells.

Cells within the microvasculature, namely endothelial cells
and pericytes, are important regulators of angiogenesis andmyogenesis, making them key players in both muscle andvascular generation following injury (2). Endothelial cells(78, 100, 111, 217, 238) and pericytes secrete various
cytokines (41, 108). Fibroblasts contribute to production of
the extracellular matrix of muscle connective tissue by secreting fibronectin, laminin, specific tenascins and neural celladhesion molecules (141). In response to muscle injury,
fibroblasts proliferate and begin to produce collagen-rich
extracellular matrix to restore the muscle’s framework (121).
Fibroblasts also secrete assorted cytokines (47, 78, 118, 136,
163). Neutrophils play an important role in breaking down
damaged muscle tissue in the acute phase of muscle injury(148, 174), whereas monocytes/macrophages regulate subsequent tissue regeneration (12, 218). Neutrophils (36, 58, 132,
187, 223) and monocytes/macrophages (8, 48, 54, 78, 93, 123,
131, 179) both secrete a variety of cytokines. As cytokine-producing cells, endothelial cells, pericytes, fibroblasts, neutrophils and monocytes/macrophages may all contribute to
global cytokine expression in skeletal muscle.

Skeletal muscle has been proposed as the dominant source of
circulating IL-6 based on the increase in the arterial-femoral
venous differences in the concentration of IL-6 (215). However, this does not provide prima facie evidence that skeletal
muscle cells are the main cell type that secretes cytokines
such as IL-6 into the circulation during exercise. Skeletal
muscle is composed of many other cell types such as fibroblasts, myeloid cells, pericytes which also secrete cytokines.
The organs and cells that secrete other cytokines (not produced in abundance by skeletal muscle cells) into the circulation during exercise remain to be determined. The resultsfrom many of these studies on cytokine secretion by leucocytes in vitro highlight the importance of how we interpret
such data. It is important to consider differences in stimulated
versus spontaneous cytokine secretion, intracellular cytokine
production versus extracellular secretion, and changes in theabsolute amount of cytokines that are secreted versus cytokine
secretion per cell.

In addition to skeletal muscle, IL-6 is also released from thebrain (158) and peritendinous tissue (114) after exercise.
Whereas IL-6 mRNA is expressed in adipose tissue following
exercise (45, 103), IL-6 is not released from adipose tissueduring exercise (126). Evidence indicates that macrophages
secrete IL-1β in the brain following downhill running (35),but it is unknown whether IL-1β is released from the brain
into the circulation during exercise. Exercise also increases
gene expression of IL-1ra and IL-15 receptorα in the liver infasting rats (30), but it remains unknown if the liver is asource of circulating cytokines after exercise.

Leucocytes are probably only a minor source of circulatingcytokines following exercise (Table 4). Studies on cytokine
production by leucocytes can be divided into those that havemeasured cytokine gene expression in leucocytes, intracellular cytokine production, and extracellular cytokine secretion.
Leucocyte mRNA expression of IL-1β, IL-1ra, IL-8 and IL-10
increases, whereas IL-6 mRNA expression remains

RegUlatiOn OF cytOKine synthesis
anD secRetiOn

Cytokine secretion by skeletal muscle cells involves various
intracellular factors, including mitogen-activated protein
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Exercise-induced cytokine responses • 15
kinases, heat shock factor 1, histone deacetylases and transcription factors such as nuclear factor of activated T cells(NFAT), activating protein (AP)-1 and NFκB (6, 70-72,
107,128, 233, 212, 235). In addition, cellular processes suchas Ca2+ signaling and protein unfolding also stimulate muscle
cells to express cytokine genes and/or secrete cytokines (92,233). Activating transcription factor 3 is an important regulator of cytokine secretion by macrophages (76), and may also
play a role in skeletal muscle cells. In comparison with ourknowledge of the factors that induce cytokine synthesis, muchless is known about the factors that restrict and/or inhibit
cytokine expression and secretion (145). In the context of
exercise, this information is important because it could
account for why IL-1β and TNF-α mRNA expression in skeletal muscle increases, yet the circulating concentrations ofthese cytokines remains comparatively low following exercise(150-152, 212). Below, we propose some potential negative
regulatory mechanisms that may govern cytokine expression
and secretion by skeletal muscle cells.

MicroRNAs
MicroRNAs also bind to the 3’ untranslated regions of transcripts (222) and interact with RNA-binding proteins to regulate the fate of mRNA (59, 98, 127). MicroRNAs such as Let7, miR-146, miR-221, miR-155 and miR-106 regulate theexpression of IL-1, IL-6, IL-8, TNF-α and IL-10 by immune
cells (21, 38, 59, 98, 170, 198, 224, 229). Skeletal muscle
cells express a number of microRNAs, including miR-133,
miR-1, miR-367, miR-135a, miR-222, miR-29a, b and c,
miR-221, miR-223 and miR-206 (34, 42, 105). MicroRNA
Let-7 inhibits the secretion of IL-13 in human myotubes (97).
Other microRNAs such as miR-367, miR-222, and miR-29
may control cytokine secretion by skeletal muscle cells indirectly by altering the activity of endothelial nitric oxide synthase (188) and signal transducer and activator of transcription (STAT) proteins (53). As more microRNAs are identifiedin skeletal muscle, this may improve our knowledge ofwhether they regulate cytokine expression and secretion byskeletal muscle cells.

Relatively little research has examined changes in the expression of RNA-binding proteins in skeletal muscle following
exercise. Hubal et al. (94) reported that mRNA expression ofzinc finger protein 36 (a member of the tristetraprolin family)
increases in skeletal muscle following exercise. This response isgreater following eccentric exercise compared with concentric
exercise, and is augmented following repeated bouts of eccentric exercise (94) which suggests a role for zinc finger protein
36 in regulating skeletal muscle adaptation following injury.
Another study observed that tristetraprolin mRNA expression
precedes that of LPS-inducible CXC chemokine mRNA expression in C2C12 myoblasts and in skeletal muscle following
freeze injury (193). Geyer et al (75) performed an elegant study
in which they induced the expression of the RNA-binding protein tristetraprolin in C2C12 myotubes. This treatment suppressed mRNA expression of MCP-1, KC (IL-8) and IL-6,
while it also reduced MCP-1 secretion following LPS stimulation. These findings highlight the need for further research togain greater insights into the role of RNA-binding proteins inregulating cytokine secretion by skeletal muscle cells.

Soluble receptors
Soluble receptors can also restrict cytokine signaling throughtwo main mechanisms. First, soluble receptors can act as a‘non-signaling sink’ that directly competes with membranebound receptors for ligand binding. If the ligand-binding
affinity of soluble receptors and membrane-bound receptors issimilar, the capacity of soluble receptors to inhibit signaling
depends on the balance between the two types of receptors(84). Soluble receptors for IL-1 and TNF-α appear to operate
in this manner (3, 10). Second, soluble receptors can arise
through the proteolytic cleavage of membrane-bound receptors. This process results in fewer membrane-bound receptors
to bind ligands and initiate cell signaling (84). TNF-α and IL6 can also induce shedding and/or endocytosis of their own
receptors (55, 79, 88, 177). These actions may represent an
autocrine negative feedback loop to prevent excess ligand
stimulation. Currently, there is insufficient evidence to determine whether soluble receptors regulate cytokine signaling inskeletal muscle following exercise. Gene expression of soluble IL-6 receptor (but not gp130) is elevated in skeletal muscle between 4.5 and 9 h after exercise (104), whereas the plasma concentration of soluble IL-6 receptor does not change(104) or only increases slightly (120). The presence of circulating soluble IL-6 receptors after exercise may depend on
proteolytic cleavage of IL-6 receptors (120). Gene expressionof TNF-α and IL-1β in skeletal muscle is elevated for up to 24
h after exercise (124, 150-152). Although the plasma concen-

RNA-binding proteins
Intracellular utilization of mRNA depends on several processes including mRNA maturation, shuttling and stability. Inturn, these post-transcriptional processes are under the controlof RNA-binding proteins and microRNAs. RNA-binding proteins regulate mRNA utilization by binding to adenine/uracylrich elements downstream of the 3’ untranslated regions oftranscripts (205). A small subset of RNA-binding proteins areactive in skeletal muscle, including human antigen R, KHtype splicing regulatory protein, CUG binding protein 1,
poly(A) binding protein, Lin-28 and tristetraprolin (9). These
RNA-binding proteins are known to regulate myogenesis (9),but they may also control cytokine translation in skeletal muscle cells. Human antigen R enhances the stability of TNF-αmRNA (49, 140). However, together with CUG binding protein 1 and tristetraprolin, human antigen R may also silence
TNF-α translation (33, 98, 101, 240). Tristetraprolin expression increases (221), whereas the expression of human antigen R decreases (181) in response to the anti-inflammatory
cytokines IL-4 and IL-10.

Suppressor of cytokine signaling (SOCS)
Surprisingly little research has investigated the role of SOCS
proteins in regulating cytokine synthesis and signaling by
skeletal muscle cells. Paradoxically, the limited evidence
available indicates that overexpression of SOCS3 increases
IL-6 transcription in myotubes (204). Under some conditions,the interaction between SOCS proteins and cytokines may bereciprocal. IL-6 and TNF-α induce SOCS3 mRNA expression
in C2 myoblasts (5) and cardiac myoblasts (230). TNF-α infusion in vivo also stimulates SOCS3 mRNA in murine muscle(60). Further research is warranted to examine in greater
detail the function of SOCS proteins as regulators of cytokine
synthesis and signaling by skeletal muscle cells.

EIR 21 2015

16 • Exercise-induced cytokine responses
trations of soluble TNF-α receptors and IL-1ra are also elevated for several hours after exercise (152, 160, 225), it isunknown whether these receptors are derived from, and are
active in skeletal muscle.

Other factors
Other factors such as IL-6 and HSP72 produced locally inskeletal muscle during exercise may also regulate cytokine
synthesis. IL-6 inhibits LPS-induced synthesis of TNF-α bymonocytes (196). In response to LPS treatment in vivo, TNFα concentration is lower in serum and broncho-alveolar
lavage fluid from IL-6+/+ mice compared with IL-6-/- mice(236). An increase in plasma IL-6 concentration following IL6 infusion or exercise inhibits the systemic release of TNF-α
in response to LPS (206). Local production of IL-6 may therefore regulate the synthesis and systemic release of TNF-α during exercise.

In addition to cytokines, endurance exercise induces HSP72mRNA expression in skeletal muscle (16). Heat exposure
increases HSP72 mRNA expression and IL-6 mRNA expression and protein synthesis in C2C12 myotubes in a temperature-dependent manner (234). As further evidence for this regulatory role of HSP72, the heat shock inhibitor Knk437 attenuates HSP72 mRNA expression, and completely blocks IL-6
mRNA expression in myotubes incubated at 42°C (234). Theinteraction between HSP72 and IL-6 appears to be reciprocal,
because IL-6 infusion induces HSP72 mRNA expression inskeletal muscle (63). Huey and Meador (95) demonstrated
that IL-6 regulates the expression of HSPs in skeletal muscle
in response to LPS, but not exercise. In direct contrast with
IL-6, heat exposure inhibits TNF-α mRNA expression in
myotubes (234) and TNF-α protein synthesis in other cell
types (61, 142). These findings implicate HSP72 as a negative
regulator of TNF-α mRNA expression and synthesis, but further research is required to confirm this notion. The upstream
regulator of HSPs, heat shock factor -1 may play a more central role than HSPs in regulating cytokine secretion by skeletal
muscle cells (233). Ohno et al (159) have also demonstrated
that acute heat stress suppresses NFκB activity in C2C12
muscle cells. This response was accompanied by increased
expression of HSP72 (159), but it remains to be determined if
HSP72 can block NFκB activity in muscle cells.

Skeletal muscle expresses the gene for tumor necrosis factor
receptor-associated factor (TRAF)-6-inhibitory zinc finger
protein (TIZ) (77). By inhibiting the activation of NFκB, cJun N-terminal kinase and AP-1 (199), zinc finger proteinssuch as TIZ may restrict cytokine secretion by skeletal muscle
cells. Similar to other factors described above, future research
could investigate the regulatory roles of zinc finger proteins inskeletal muscle.

In another interesting study, Lee (119) demonstrated thattreatment of C2C12 myotubes with IGF-1 inhibited mRNA
expression of IL-6 and TNF-α. This effect was due to suppression of TLR4 signaling, which was in turn mediated by inhibition of the PI3K/Akt signaling pathway (119). These findings
provide further evidence of potential autocrine loops andcross-talk between cytokines and growth factors within skeletal muscle.
EIR 21 2015

Cytokine trafficking and secretion
In contrast with cells of the immune system, regulation ofcytokine trafficking and secretion in muscle cells remains
largely unknown. Hoier et al (90) made the first attempt tocharacterize the subcellular localization of VEGF in skeletal
muscle. However, they did not investigate dynamic changes
in trafficking of VEGF within muscle cells. Lauritzen et al(116) have provided the most detailed insights to date on themechanisms of cytokine secretion by skeletal muscle fibers.
Stow and Murray (216) have provided a comprehensive
overview on the mechanisms of trafficking and secretion in
immune cells, and this may be used as a guide to new researchin muscle cells.

RegUlatiOn OF cytOKine
exPRessiOn anD secRetiOn in
MyOBlasts veRsUs MyOtUBes

As noted previously, and summarized in Table 2, the constitutive expression of cytokines varies between myoblasts andmyotubes. Below we discuss some of these differences, someof the mechanisms that may govern alterations in cytokine
expression and secretion by skeletal muscle cells as they differentiate, and the possible biological significance of thesedifferences.

Gene expression of numerous chemokines and their receptors
increases markedly after 16−48 h of differentiation (80). Of
note, MCP-1 mRNA expression peaks at 16 h, whereas TNFα mRNA expression increases 10-fold between 16 and 24 hand declines thereafter (80). Several studies indicate thatmyoblasts and myotubes constitutively express similar levelsof IL-6 mRNA. However, compared with myotubes,
myoblasts produce substantially more IL-6 protein upon stimulation with IL-1β, TNF-α and LPS (71, 144, 178). In
response to TNF-α and LPS, myoblast production of IL-6
increases in a linear manner, whereas myotube production of
IL-6 increases in a more ‘bell-shaped’ manner (178). The
greater sensitivity of myoblasts to pro-inflammatory stimuli
such as TNF-α and LPS may reflect the requirement formyoblasts to secrete factors such as IL-6 to promote myoblast
proliferation (13, 110), and therefore, muscle regeneration(178). Protein expression of MCP-1 (85), IL-6 (15) and LIF(25) also increases during the first 24−48 h of differentiation.
Protein expression of IL-7 and IL-15 increases more steadily
between 2−7 d of differentiation (83, 180). Protein expressionof IL-1β and IL-1ra (14) and MCP-1 secretion (40) increase
after 12−16 d of differentiation. Gene and protein expression
BDNF expression decreases after 4 d (143).

The factors responsible for changes in cytokine expression byskeletal muscle cells as they differentiate are uncertain. Someof the factors that regulate cytokine expression in skeletal
muscle cells (e.g., mitogen-activated protein kinases, histone
deacetylases, NFAT and NFκB) also control muscle cell differentiation (11, 15, 139, 169), and may therefore account foralterations in cytokine expression and secretion in skeletal
muscle cells as they differentiate. The expression of some tolllike receptors (e.g., TLR2, TLR5) increases during muscle celldifferentiation (24), which may also influence signaling path-Exercise-induced cytokine responses • 17
ways linked to cytokine expression and secretion in skeletal
muscle cells (69). Changes in cytokine expression during muscle cell differentiation appear to play an important functionalrole. For example, increased expression of IL-6 (15) andreduced expression of BDNF (143) in skeletal muscle cells isnecessary for them to differentiate. Conversely, increased
expression of TNF-α during muscle cell differentiation (80)
may inhibit myoblast differentiation (115, 227), although thiseffect is not entirely consistent (43). Using an RNAi screen,
Ge et al (74) identified more than 100 cytokines that act regulate myoblast differentiation. Based on their results, they wereable to classify these cytokines according to their capacity toinitiate differentiation, regulate myocyte fusion and inhibit differentiation. Increased chemokine expression during differentiation may also control the migration and/or positioning ofmyoblasts so that they can successfully fuse with nascent
myotubes (80). Alternatively, increased cytokine expression
during muscle cell differentiation may promote muscle cellproliferation (122, 237), and migration of monocytes (40) andmesenchymal stem cells (176) to support muscle growth. Last,
autocrine cross-talk between cytokines may also control muscle cell differentiation (4, 7, 71, 125).

cOnclUsiOn

Our understanding of the importance of skeletal muscle andcytokines as mediators of metabolism has increased substantially over the last decade or so. Research to date has identified more than 600 different proteins that are secreted byskeletal muscle cells (168). In this rapidly advancing age of ‘omics’ technologies, the muscle cell secretome will continue
to grow and provide new targets on which to focus. We now
know that myokines exert various endocrine effects on various metabolically active organs, including adipose tissue, theliver, the pancreas and the brain. Nevertheless, perhaps withthe exception of IL-6 and LIF, our knowledge of the factors
and mechanisms that regulate cytokine production and releasefrom skeletal muscle cells during exercise remains somewhat
limited. Skeletal muscle cells produce numerous cytokines in
response to various agents, but not all these agents are present
at similar concentrations and/or are active in the muscle
microenvironment during exercise. The capacity for these
individual agents to stimulate skeletal muscle cells to produce
cytokines is well characterized. However, the control ofcytokine production in skeletal muscle during exercise ismore complex than the in vitro setting, and depends on interactions between a variety of local and systemic factors. Future
research should aim to treat skeletal muscle cells with combinations and concentrations of agents that are present in skeletal muscle during exercise.

Cyclic strain and electromagnetic stimulation of skeletal muscle myotubes in vitro has generated useful insights into thesignaling pathways that govern cytokine production by skeletal muscle cells during exercise. Adding other factors—suchas cytokines themselves—to this experimental system could
simulate the muscle microenvironment during exercise. In
doing so, this approach may assist in characterizing interactions between factors that stimulate or inhibit the ability ofskeletal muscle cells to produce cytokines during exercise.

More research is warranted to identify the feedback mechanisms that govern cytokine synthesis by skeletal muscle cells;in particular, which mechanisms are most important, how theyinteract with each other, and how they are induced and regulated. These research endeavors are important for several reasons. First, this information may help to understand the factors governing the systemic release of cytokines. Second, thisinformation may help to understand the processes that regulate acute inflammatory responses to tissue injury. Last, thisinformation may help to determine why some pro-inflammatory cytokines are chronically elevated in skeletal muscle ofpatients with idiopathic myopathies, rheumatoid arthritis andmuscular dystrophy.

Finally, much has been written about the anti-inflammatory
effects of exercise. Petersen et al (171) first proposed thenotion that exercise-induced increases in IL-6, IL-1ra and IL10 exert beneficial anti-inflammatory effects to counteract
obesity and insulin resistance. Although this theory is appealing from a mechanistic perspective (206), cytokines may playa relatively minor role in regulating the health benefits ofexercise training. Evidence in support of this notion is thatbrisk walking does not stimulate any discernible increase incirculating cytokines (135), yet regular walking is associatedwith many health benefits. Furthermore, marathon runninginduces high physiological stress and a large cytokine
response (155), but it is doubtful the cytokines are increased
for the purposes of health. Instead, exercise-induced cytokinechanges may represent a more generalized response to internal and/or external stress. Factors such as oxidative or
nitrosative stress, damaged or unfolded proteins, hyperthermia or energy imbalance likely induce cytokine production
during exercise through catecholamines, endotoxin, alarmins,
ATP and pro-inflammatory cytokines themselves (232). Theseissues highlight the need for further research to enhance ourunderstanding of the biological significance of exerciseinduced cytokine responses.

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