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Skeletal Muscle as an Endocrine Organ: The Role

of Myokines in Exercise Adaptations
Christoph Hoffmann1 and Cora Weigert1,2,3

1
Division of Pathobiochemistry and Clinical Chemistry, Department of Internal Medicine IV, University
Hospital Tübingen, 72076 Tübingen, Germany
2
Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University
of Tübingen, 72076 Tübingen, Germany
3
German Center for Diabetes Research (DZD), 85764 München-Neuherberg, Germany
Correspondence: cora.weigert@med.uni-tuebingen.de
Exercise stimulates the release of proteins with autocrine, paracrine, or endocrine functions
produced in skeletal muscle, termed myokines. Based on the current state of knowledge, the
major physiological function of myokines is to protect the functionality and to enhance the
exercise capacity of skeletal muscle. Myokines control adaptive processes in skeletal mus-
cle by acting as paracrine regulators of fuel oxidation, hypertrophy, angiogenesis, inflamma-
tory processes, and regulation of the extracellular matrix. Endocrine functions attributed to
myokines are involved in body weight regulation, low-grade inflammation, insulin sensitiv-
www.perspectivesinmedicine.org
ity, suppression of tumor growth, and improvement of cognitive function. Muscle-derived

regulatory RNAs and metabolites, as well as the design of modified myokines, are promising
novel directions for treatment of chronic diseases.
he importance of regular physical activity to activity for health” (WHO 2010). These well-
T prevent and treat chronic and degenerative
diseases is widely accepted. This does not only
acknowledged benefits of exercise go far beyond
the molecular adaptations of working skeletal
include metabolic diseases such as type 2 diabe- muscle and include enhanced substrate delivery
tes and morbid obesity but most if not all wide- and oxidation capacity and increased mechani-
spread and common diseases of the increasing- cal strength and power (Egan and Zierath 2013).
ly aging society worldwide. There is growing For decades, researchers have focused on eluci-
evidence that regularly performed exercise is a dating the mechanisms by which the energy-de-
powerful therapy against the progression of car- manding mechanical work of skeletal muscle
diovascular diseases, cancer, neurodegenerative can impact the entire body to promote profound
diseases, psychiatric disorders, and chronic pul- health benefits. In 1961, Goldstein conducted
monary diseases (Pedersen and Saltin 2015). For cross-transfusion experiments between resting
prevention of these noncommunicable diseases, dogs and dogs in which muscle contraction
the World Health Organization (WHO) has de- was induced by electrical stimulation (Goldstein
veloped “global recommendations on physical 1961). Based on his data, he postulated the exis-
Editors: Juleen R. Zierath, Michael J. Joyner, and John A. Hawley

Additional Perspectives on The Biology of Exercise available at www.perspectivesinmedicine.org
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Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029793
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C. Hoffmann and C. Weigert
tence of humoral components induced by mus- of secreted proteins (Hittel et al. 2009; Bouzakri
cular work that enhance glucose utilization in et al. 2011; Le Bihan et al. 2012; Hartwig et al.
the resting dogs. In 1983, a pyrogenic substance 2014). About two-thirds of the more than 1000
with an estimated molecular weight of 14 kDa proteins identified in cultured primary human
was reported in human plasma after 1 h of bi- myotube secretome were predicted or have been
cycling, although a specific factor could not be annotated as putative secreted proteins, under-
identified (Cannon and Kluger 1983). The de- lining the potency of skeletal muscle to act as an
tection of increased expression of the cytokine endocrine organ (Weigert et al. 2014). Function-
interleukin 6 (IL-6) in human muscle biopsies al term analysis of these proteins suggests an
obtained following exercise (Ostrowski et al. important paracrine function in skeletal muscle
1998b) and the concomitant release of this mus- development and regeneration, extracellular
cle-derived IL-6 into the circulation (Steensberg matrix (ECM) organization, and angiogenesis.
et al. 2000) was then the starting point for a new At least a part of the proteins not assigned as
research field. The concept of myokines was in- potentially secreted forms are carried in micro-
troduced to describe putative cytokines that are vesicles such as exosomes (Le Bihan et al. 2012).
produced and released by muscle fibers and ex- To investigate exercise-regulated myokines,
ert endocrine effects (Pedersen et al. 2003). analyses of transcripts in exercised human skel-
Since then, the list of myokines is constantly etal muscle were combined with profiling of
growing and the classification has become secreted proteins in cultured muscle cells
more loosely interpreted to include any secreted (Norheim et al. 2011) or quantification of my-
protein that is produced in skeletal muscle okine plasma levels (Catoire et al. 2014b). In
whether it acts in an autocrine, paracrine, or vitro exercise by applying electric pulse stimu-
endocrine manner (Pedersen and Febbraio lation to cultured human skeletal muscle cells
2012). The focus of this review is on exercise- was used for antibody-based microarray profil-
regulated myokines and does not touch on the ing of the supernatant (Raschke et al. 2013a;
numerous myokines that have been described Scheler et al. 2013). None of these studies
in differentiating skeletal muscle cell cultures came close to providing a complete picture of
(Henningsen et al. 2010; Chan et al. 2011) in the exercise-induced release of myokines into
the context of muscle injury (Zeng et al. 2010) muscle interstitial fluid or the circulation. One
or mitochondrial dysfunction (Ost et al. 2016). explanation is that plasma and interstitial fluid
We will give an overview on the current knowl- represent two of the most challenging secre-
edge of human myokines and discuss the evi- tomes for proteomics profiling, because a few
dence for an autocrine, paracrine, or endocrine highly abundant protein species are responsible
role in the health-promoting effects of exercise for 99% of the protein content and these dis-
and the potential therapeutic options. guise other proteins such as cytokines of com-
parably very low concentration in the picomolar
or femtomolar range (Anderson and Anderson
THE HUMAN SKELETAL MUSCLE
2002). To circumvent this problem, different ap-
SECRETOME
proaches have been developed and are currently
The idea of endogenous factors that are released optimized to enrich the low abundant proteins
from human skeletal muscle as hormone-like (Frobel et al. 2015; Gianazza et al. 2016).
mediators of the preventive and therapeutic ef- The majority of the hitherto assigned exer-
fects of exercise has initiated proteomics and cise-regulated myokines with putative endo-
transcriptomics profiling approaches to eluci- crine functions were identified by targeted ap-
date the composition of the skeletal muscle se- proaches analyzing transcript and protein level
cretome and to identify novel myokines. Global in human skeletal muscle biopsies and plasma
and targeted proteomic profiling was applied to following one acute bout of exercise or after
the secretome of cultured primary human my- training. An overview of exercise-regulated hu-
otubes to provide a comprehensive description man myokines with exercise-mediated changes
2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029793
Myokines in Exercise Adaptations
in mRNA and protein abundance in skeletal stitial fluid can be seen after 30 min of one-
muscle or plasma is given in Table 1. The pro- legged knee extensor exercise or rowing and
teins secreted by skeletal muscle can often be may occur independent of a transcriptional re-
released from a wide variety of cells, including sponse (Rosendal et al. 2005; Rue et al. 2014).
immune cells, endothelial cells, fibroblasts, os- However, elevated transcript or protein levels
teocytes, hepatocytes, and adipocytes. There- are not always paralleled by increased systemic
fore, elevated systemic concentrations of these concentrations, as reported for CTGF, CYR61,
proteins after exercise or in the supernatant of IL-8, IL-15, LIF, and VEGF (Ostrowski et al.
primary human muscle cells only suggest, and 1998a; Nieman et al. 2003; Broholm et al.
do not prove, the existence of an exercise-regu- 2011; Catoire et al. 2014b; Landers-Ramos
lated myokine. The list is dominated by cyto- et al. 2014). In general, systemic cytokine re-
kines, growth factors, and regulators or compo- sponses are more pronounced after exercise
nents of the ECM. with a higher degree of muscle damage such
Moreover, transgenic expression of tran- as downhill running, eccentric exercise, and re-
scriptional key regulator peroxisome prolifera- sistance training (Paulsen et al. 2012). More-
tor-activated receptor coactivator (PGC)1a in over, a robust elevation of the transcript abun-
skeletal muscle led to the discovery of irisin and dance of several cytokines and chemokines in
meteorin-like as exercise-regulated myokines skeletal muscle is regularly described after exer-
that stimulate energy expenditure and brown cise bouts with long duration or high intensity
fat – like development in mice (Bostrom et al. (Nieman et al. 2001; Suzuki et al. 2006; Neu-
2012; Rao et al. 2014). Meteorin-like as well as bauer et al. 2014) but less pronounced or absent
myonectin (CTRP15) (Seldin et al. 2012) and after more moderate intense physical activity
musclin (OSTN) (Subbotina et al. 2015) have (Catoire et al. 2014b; Hansen et al. 2015b). No-
only been described in rodent studies, and hu- tably, the increased expression and release of
man data on the regulation of intramuscular IL-6 and to some extent of other cytokines
and systemic levels of these proteins following occurs independent of muscle damage. The
exercise have not been reported to date. increase in IL-6 is not linked to the release in
tumor necrosis factor a (TNF-a) (Steensberg et
al. 2002; Keller et al. 2006) or other markers of
EXERCISE-REGULATED HUMAN MYOKINES
tissue injury (Croisier et al. 1999; Starkie et al.
Experimental evidence for an exercise-induced 2001) but is regulated by carbohydrate availabil-
production in and secretion from human mus- ity and proposed to serve as a sensor of the
cle is provided for several cytokines, including metabolic status of the muscle (Keller et al.
IL-6, IL-8, IL-10, IL-15, CC-chemokine ligand 2001; Steensberg et al. 2001; MacDonald et al.
(CCL)2, IL-1 receptor antagonist, calprotectin 2003). Low muscle glycogen content preexercise
S100A9, and vascular endothelial growth factor results in higher IL-6 and IL-8 transcript levels
(VEGF) with increased interstitial fluid concen- postexercise (Chan et al. 2004). Furthermore,
trations in skeletal muscle following exercise or carbohydrate ingestion before exercise attenu-
a net release from skeletal muscle measured as ates the increase in these transcripts (Nieman
arterial– venous differences (see Table 1 for de- et al. 2003). In addition, a recent study in ro-
tails). At least increased mRNA and protein dents shows that the release of the bone-derived
abundance in human skeletal muscle following hormone osteocalcin induces part of the exer-
acute exercise or training is described for angio- cise-induced increase in IL-6 and enhanced
poietin-like 4 (ANGPTL4), brain-derived neu- substrate oxidation capacity (Mera et al.
rotrophic factor (BDNF), connective tissue 2016), which shows the ability of bone to sense
growth factor (CTGF), cysteine-rich angiogenic mechanical forces and to act as regulator of my-
protein 61 (CYR61), fractalkine, and nicotin- okines in response to exercise.
amide phosphoribosyl transferase (NAMPT). Not all of the exercised-regulated cytokines
An increase of cytokines in the muscular inter- are localized to myofibers; satellite cells, fibro-
Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a029793 3
4
Table 1. Regulation of myokines following exercise in humans
Response to exercise (E) or training (T) in humansb
Release: cultured
Myokine muscle cellsa Muscle mRNA Muscle protein Plasma/serum Muscle release
ANGTPL4 Staiger et al. 2009 E: Catoire et al. 2014a E: Catoire et al. 2014a E: Kersten et al. 2009
Apelin Besse-Patin et al. 2014 T: Besse-Patin et al. 2014 T: Kadoglou et al. 2012
BDNF Le Bihan et al. 2012 E: Matthews et al. 2009 E: Matthews et al. 2009 E: Ferris et al. 2007; Saucedo
Marquez et al. 2015
CCL2 Raschke et al. 2013a; E: Tantiwong et al. 2010; Catoire E: Hubal et al. 2008; Della E: Peake et al. 2005; Int Rue et al. 2014
Scheler et al. 2013 et al. 2014b Gatta et al. 2014 Andersson et al. 2010
CHI3L1 Le Bihan et al. 2012; E: Gorgens et al. 2016 E: Gorgens et al. 2016
Hartwig et al. 2014
CTGF Le Bihan et al. 2012; E: Heinemeier et al. 2013; Catoire E: Kivela et al. 2007
Hartwig et al. 2014 et al. 2014b
CTSB Norheim et al. 2011; T: Norheim et al. 2011 T: Moon et al. 2016
Hartwig et al. 2014
CYR61 E: Catoire et al. 2014b; Hansen E: Kivela et al. 2007
et al. 2015b
Decorin Kanzleiter et al. 2014 E: Heinemeier et al. 2013 E: Kanzleiter et al. 2014
Fractalkine E: Catoire et al. 2014b; Della E: Stromberg et al. 2016 E: Catoire et al. 2014b
Gatta et al. 2014
FSTL1 Gorgens et al. 2013 T: Norheim et al. 2011 E: Gorgens et al. 2013
IGF1 Le Bihan et al. 2012 E: Bamman et al. 2001; Hameed E: Bang et al. 1990; Cappon A-V Brahm et al.
et al. 2003 et al. 1994 1997
Int Berg et al.
2007
IL-6 Bartoccioni et al. 1994 E: Ostrowski et al. 1998b E: Hiscock et al. 2004 E: Ostrowski et al. 1998a A-V Steensberg
et al. 2000
Int Rosendal et al.
2005
IL-7 Haugen et al. 2010 T: Haugen et al. 2010 E: Andersson et al. 2010
IL-8 Raschke et al. 2013a; E: Chan et al. 2004; Louis et al. E: Della Gatta et al. 2014 E: Nieman et al. 2001; Int Rue et al. 2014
Scheler et al. 2013 2007; Covington et al. 2016 Andersson et al. 2010
Continued
Table 1. Continued
Response to exercise (E) or training (T) in humansb
Release: cultured
Myokine muscle cellsa Muscle mRNA Muscle protein Plasma/serum Muscle release
IL-10 Scheler et al. 2013; E: Nieman et al. 2003 E: Smith et al. 2000 Int Rue et al. 2014
Hartwig et al. 2014
IL-15 Raschke et al. 2013a E: Nielsen et al. 2007 T: Rinnov et al. 2014 E: Riechman et al. 2004; Int Pierce et al.
Tamura et al. 2011 2015
IL-1RN E: Nieman et al. 2003 E: Ostrowski et al. 1998a; Int Rue et al. 2014
Peake et al. 2005
Irisin T: Bostrom et al. 2012 T: Jedrychowski et al. 2015
LIF Broholm et al. 2011 E: Broholm et al. 2008;
Covington et al. 2016
Myostatin Hittel et al. 2009 E,T: Louis et al. 2007; Heinemeier T: Hittel et al. 2010 T: Walker et al. 2004; Hittel
et al. 2013; Hjorth et al. 2016 et al. 2010
NAMPT Le Bihan et al. 2012 T: Alfieri et al. 2015 T: Costford et al. 2010; E: Ghanbari-Niaki et al. 2010
Brandauer et al. 2013
S100A9 E: Mortensen et al. 2008 E: Fagerhol et al. 2005; A-V Mortensen
Mooren et al. 2006 et al. 2008
SPARC Norheim et al. 2011 T: Hjorth et al. 2015 E: Aoi et al. 2013
VEGF Raschke et al. 2013a; E: Gavin et al. 2004 E: Hoier et al. 2013 E: Wahl et al. 2011 Int Hoier et al.
Scheler et al. 2013 2013
E:(), increased (decreased) following acute exercise; T:(), increased (decreased) following training; A-V, net release into plasma
from the exercising muscle; Int, increased concentration in the interstitial fluid of the exercising muscle during or following acute exercise;
mRNA, messenger RNA.
a
Release from unstimulated human skeletal muscle cells in vitro.
b
Shown are only the studies in which regulation of the respective myokine following exercise or training was detected. When numerous
studies exist, only one of the first significant contributions is included.
5
Immune cells Fibroblasts

Recruitment ECM production
Activation
Endothelial cells
Proliferation
Migration
CCL2
Fractalkine CTGF
TGF-β ECM
IL-10
Organization
MMPs Remodeling
Cathepsins
VEGF IL-8 CYR61 SPARC
Endocrine effects Muscle’s
secretome FSTL1
(see Fig. 2)
Myostatin
IL-7 Decorin
LIF IGF-1
IL-6 TGF-β
TGF-β Apelin
Capillary
IGF-1 IL-15
Myostatin IL-6
Myofibers
Substrate oxidation
Hypertrophy
Satellite cells
Basal lamina Proliferation
Differentiation
Figure 1. Autocrine and paracrine effects of exercise-regulated human myokines. Myofibers, satellite cells,
fibroblasts, immune cells, and endothelial cells contribute to the secretome of muscle, which also includes
proteins of the extracellular matrix (ECM). Shown are the autocrine and paracrine functions of exercise- or
training-regulated human myokines on the different cell types and structures within muscle tissue. The effect of
myokines can be both stimulatory or inhibitory. CCL2, CC-chemokine ligand 2; CTGF, connective tissue growth
factor; TGF-b, transforming growth factor b; IL, interleukin; MMPs, matrix metalloproteinases; VEGF, vascular
endothelial growth factor; SPARC, secreted protein rich in cysteine; FSTL1, follistatin-like 1; LIF, leukemia
inhibitory factor; IGF-1, insulin-like growth factor 1. (Figure created using illustrations provided by Servier
Medical Art.)
blasts, endothelial cells, and macrophages resid- spective of the validation of myofibers as origin
ing in muscle tissue can contribute to muscular of the released protein.
abundance and release of proteins (Fig. 1). IL-6
is primarily localized in myofibers (Hiscock
IL-6—A MULTITALENTED MYOKINE
et al. 2004), but also detected in satellite cells
(McKay et al. 2009) and fibroblasts (Malm et al. IL-6 is the best-studied myokine and can serve
2004). CCL2 is detected in macrophages and as a prime example for the potential of exercise-
satellite cells (Hubal et al. 2008; Della Gatta regulated myokines with well-described auto-,
et al. 2014), LIF in endothelial cells (Malm para-, and endocrine effects. Acting in an auto-
et al. 2004), IL-8 in macrophages and blood crine/paracrine manner in skeletal muscle, IL-
vessels (Della Gatta et al. 2014), and fractalkine 6-dependent STAT3 signaling was detected in
in the endothelium (Stromberg et al. 2016). human satellite cells after muscle-lengthening
VEGF is localized to myofibers, endothelial contraction (Toth et al. 2011). IL-6 is important
cells, and pericytes (Hoier et al. 2013). It is com- for hypertrophic muscle growth and myogene-
mon practice to use the term “myokine” irre- sis in mice (Serrano et al. 2008). Myotube for-
mation is reduced in IL-6-deficient primary al. 2004). Myostatin received new attention as a
mouse skeletal muscle cells (Hoene et al. potential target to treat the metabolic syndrome
2013). Endocrine effects assigned to the exer- because myostatin transcript levels are higher in
cise-induced release of IL-6 fit into the concept skeletal muscle of type 2 diabetes patients (Pals-
of health-promoting myokines. IL-6 increases gaard et al. 2009) and myostatin plasma levels are
insulin-stimulated glucose disposal and glucose elevated in obese women (Hittel et al. 2009).
oxidation (Carey et al. 2006) and stimulates li- Regular exercise reduces myostatin transcript lev-
polysis and fat oxidation (van Hall et al. 2003; els in skeletal muscle of obese subjects and people
Petersen et al. 2005). On the molecular level, with impaired glycemic control, but decreased
these effects are mediated via IL-6-dependent mRNA abundance was also found after one acute
activation of AMP-activated protein kinase bout of exercise in healthy people (Table 1). My-
(AMPK) (Ruderman et al. 2006), regulation ostatin deficiency or inhibition of myostatin sig-
of insulin receptor substrate-1 (Weigert et al. naling improves insulin resistance in old and
2006), and PI3-kinase (Al Khalili et al. 2006). obese mice (Zhao et al. 2005; Wilkes et al. 2009;
Rodent studies provide evidence that IL-6 Camporez et al. 2016). The underlying mecha-
enhances expansion of pancreatic a cells (El- nisms are not completely clear, because direct
lingsgaard et al. 2008) and improves insulin effects of myostatin on insulin signaling in skel-
secretion and hyperglycemia via stimulation of etal muscle cells or adipocytes could not be de-
glucagen-like peptide 1 (GLP1) secretion from tected (Hjorth et al. 2016).
the L cells in the intestine and pancreatic a cells
(Ellingsgaard et al. 2011). IL-6 promotes the
ROLE OF MYOKINES IN EXERCISE
alternative activation of macrophages, which is
ADAPTATIONS
involved in the protection from obesity-in-
duced tissue inflammation and insulin resis- Myokines are involved in many of exercise-in-
tance (Mauer et al. 2014). Recently, exercise duced adaptations. In the following sections,
was reported to reduce tumor size and growth the potential contribution of myokines to an
in mice via IL-6-dependent natural killer cell enhanced exercise capacity and the benefits for
mobilization (Pedersen et al. 2016). To con- whole-body metabolism and prevention of
clude, the exercise-induced release of IL-6 may chronic diseases is presented. To date, function-
partly account for important beneficial effects al data are mainly based on mouse and in vitro
of exercise, including improved glycemic con- studies.
trol, loss of fat mass, suppression of tumor
growth, and maintenance of muscle mass.
Regulation of Metabolic Pathways
The beneficial effect of exercise on glycemic
MYOSTATIN—RENEWED INTEREST
control and lipid homeostasis was one of the
IN AN “OLD” MYOKINE
initial driving forces in searching for muscle-
The first identified myokine, even though not derived factors as “exercise-mimetics” for the
termed a myokine at the time of its discovery, treatment of metabolic disorders such as type
was myostatin (McPherron et al. 1997). Myosta- 2 diabetes. Besides the exercise-induced acute
tin is the myokine with probably the most pro- increase in IL-6 and the reduction in myostatin,
nounced effects on muscle mass and body fat other exercise-regulated myokines play a poten-
composition. Myostatin is expressed and secret- tial role in the regulation of metabolism follow-
ed by skeletal muscle and acts as a negative reg- ing exercise.
ulator of skeletal muscle growth (McPherron The exercise-induced increase in ANGPTL4
et al. 1997). Mutations in the human MSTN plasma levels has been involved in the regulation
gene leading to reduced production of mature of plasma triglycerides by decreasing lipopro-
myostatin protein increase muscle mass with a tein lipase (LPL) activity (Dijk et al. 2016) and
concomitant loss of adipose tissue (Schuelke et promoting adipose tissue lipolysis (Gray et al.
2012). Beyond that, ANGPTL4 was recently de- insulin sensitivity. Further exercise adaptations
scribed in mice as mediator of hyperplasia of presented in the next sections, such as the in-
pancreatic a cells (Ben Zvi et al. 2015). Apelin crease in muscle mass, the increase in muscle
is a ligand of the G-protein-coupled receptor capillarization, and the reduction in systemic in-
APJ. In rodents, apelin increases glucose uptake flammation also contribute to the improvement
and mitochondrial oxidative capacity in skeletal in substrate oxidation and glycemic control.
muscle (Dray et al. 2008; Attane et al. 2012).
However, the contribution of skeletal muscle-
The Anti-Inflammatory Effect of Exercise
derived apelin to plasma levels is questionable
(Yamamoto et al. 2011). IL-15 signaling might From the first report regarding the production
be involved in regulation of muscle fiber com- and release of inflammatory cytokines by con-
position, contractility, and body fat composi- tracting skeletal muscle, the notion that exercise
tion. Mouse models lacking the IL-15a receptor induces muscle damage and inflammation has
in skeletal muscle suggest an intramuscular role been discussed. An important paracrine func-
for IL-15 in defining the shift to fast glycolytic tion of these cytokines in the muscle is to attract
fibers, with the loss of IL-15a receptor signaling immune cells to control inflammatory process-
increasing oxidative exercise capacity and resis- es and to support muscle regeneration follow-
tance to fatigue (Pistilli et al. 2011). Conversely, ing exercise. CCL2, also known as monocyte
transgenic mice with skeletal muscle overex- chemotactic protein (MCP)1, and fractalkine,
pression of IL-15 also have a high endurance also known as chemokine (C-X3-C motif ) li-
capacity (Quinn et al. 2013). Moreover, mice gand (CX3CL)1, regulate migration and infil-
with oversecretion of IL-15 from skeletal muscle tration of monocytes and macrophages. These
showed increased lean body mass and decreased factors are involved in the recruitment of mac-
body fat content (Quinn et al. 2009). NAMPT is rophages and other immune cells in muscle and
the rate-limiting enzyme in the NAD salvage are important for tissue repair following in-
pathway responsible for converting NAM to juries (Pillon et al. 2012). IL-10 and the IL-1
NAD. Increased NAMPT protein levels in skel- receptor antagonist are part of the anti-inflam-
etal muscle following training are related to matory response counteracting the function of
enhanced mitochondrial density in athletes other cytokines on multiple levels (Maynard
(Costford et al. 2010; Brandauer et al. 2013). and Weaver 2008). Moreover, muscle-specific
However, the increase in intracellular NAMPT overexpression of IL-10 prevents diet-induced
is probably not associated with a regulation of inflammation and insulin resistance (Hong
extracellular eNAMPT, also known as Visfatin et al. 2009).
(Revollo et al. 2007). Irisin is cleaved from the The anti-inflammatory potential of exercise
fibronectin type III domain-containing protein is reflected by the decrease in systemic concen-
5 (FNDC5) and induces browning of white fat trations of several inflammatory cytokines fol-
and thermogenesis in mice (Bostrom et al. lowing training interventions, which is particu-
2012). After its discovery in mice, the existence larly observed in chronic diseases that are
of irisin in humans was questioned (Raschke associated with a low grade systemic inflamma-
et al. 2013b), and questions were raised regard- tory state such as obesity and insulin resistance,
ing the validity of the commercial ELISA kits cardiovascular diseases, atherosclerosis, and
used for quantification of human irisin (Al- neurodegenerative disorders (Gleeson et al.
brecht et al. 2015). Recently, irisin was identified 2011; Lancaster and Febbraio 2014). The reduc-
in human plasma by mass spectrometry (Jedry- tion in systemic levels of proinflammatory cyto-
chowski et al. 2015). kines is mediated by multiple mechanism
To conclude, several myokines have been including a reduction in visceral fat mass, in-
implicated in the reduction of subcutaneous creased production and release of anti-inflam-
and visceral fat and enhanced substrate oxida- matory cytokines IL-10 and IL-1 receptor
tion capacity, two main effectors of whole-body antagonist presumably via IL-6 (Steensberg
et al. 2003), down-regulation of toll-like recep- Regulation of Myogenesis and Muscle

tor signaling (Stewart et al. 2005; Oliveira and Hypertrophy
Gleeson 2010), a shift in the monocyte pop-
Increases in muscle mass and muscle hypertro-
ulations in blood to a less proinflammatory
phy are important adaptations to regular train-
phenotype (Timmerman et al. 2008), and acti-
ing, in particular to resistance exercise. The
vation of immune suppressive T cells (Yeh et al.
insulin-like growth factor 1 (IGF-1) locally in-
2006). Other myokines such as IL-7 or CHI3L1
creases in exercising muscle and is proposed to
may contribute as well to the anti-inflammatory
mediate some of the effects of training on mus-
effects (Schluns et al. 2000; Gorgens et al. 2014),
cle mass by promoting hypertrophy (Velloso
but the specific contribution of single myokines
2008). Other exercise-regulated myokines in-
to the anti-inflammatory effect of exercise is
crease the proliferation of primary human skel-
difficult to unravel because of their multiple
etal muscle cells, including decorin (Li et al.
sources and their tightly interacting network.
2007), LIF (Broholm et al. 2011), and CHI3L1
The exercise-induced release of inflam-
(Gorgens et al. 2016) or, as already mentioned
matory cytokines can be seen as a hormetic
for IL-6 and is also shown for IL-7, are involved
mechanism, that is, a beneficial response to a
in myogenesis (Haugen et al. 2010). The re-
stress-inducing condition involved in the im-
duced abundance of the muscle growth inhibi-
provement of exercise capacity, substrate oxida-
tor, myostatin, in trained skeletal muscle and
tion, and the anti-inflammatory effect of regular
altered regulation of myostatin activity can
performed exercise. In this regard, interfering
also contribute to muscle hypertrophy. Decorin
with the exercise-induced inflammation by non-
enhances skeletal muscle regeneration in mice
steroidal anti-inflammatory drugs (NSAIDs) can
by inhibiting myostatin and increasing promyo-
reduce the acute increase in skeletal muscle pro-
genic factors (Kanzleiter et al. 2014).

tein synthesis (Trappe et al. 2002) and the acti-
vation of satellite cells (Mikkelsen et al. 2009);
but studies investigating the effect of chronic
Adaptation of the Vascular System
consumption of NSAIDs during training on
the gain in muscle mass or strength showed no Exercise training induces pronounced systemic
interference or even a beneficial effect in older cardiovascular adaptations, such as increased
adults (Trappe et al. 2011; Jankowski et al. cardiac output and enhanced blood volume.
2013). In rodent studies, NSAID treatment has Muscle-derived factors have been implicated
in general negative effects on muscle regenera- in mediating the local effects of exercise training
tion, muscle hypertrophy, but also on mito- to increase capillarization in skeletal muscle and
chondrial adaptations (Machida and Takemasa improve oxygen supply and utilization (Hoier
2010; Urso 2013). These data support a role of and Hellsten 2014). The most important angio-
the exercise-induced inflammatory response genic factor induced in skeletal muscle on acute
beyond immune modulatory functions. The exercise is VEGF (Olfert et al. 2016). On a sys-
importance of cellular stress signals in the temic level, plasma VEGF levels are often unal-
health-promoting effects of exercise is further tered in response to exercise, pointing toward
emphasized by the adverse effects of antioxidant primarily local effects (Landers-Ramos et al.
treatments during training, which reduce the 2014). CYR61 or CCN1 and CTGF or CCN2
improvement of muscle mitochondrial func- belong to a family of ECM-associated proteins.
tion and insulin sensitivity, implicating the gen- Both are localized to capillaries, and CYR61 is
eration of reactive oxygen species as mediators also present in myofibers (Kivela et al. 2007).
of exercise adaptations (Ristow et al. 2009; Stro- Like VEGF, local increases in CYR61 and
bel et al. 2011). Whether an altered myokine CTGF following exercise are well-described,
response is involved in the undesired effects of whereas no elevation on the systemic level has
NSAIDs and antioxidant treatment during ex- been described. Both regulate angiogenesis, in
ercise remains to be proven. part by promoting VEGF expression, endothe-
lial cell function, and the ECM (Perbal 2004). models, two muscle-derived factors have been
IL-8 activates endothelial cell proliferation and linked to increased BDNF abundance in the
capillary tube organization (Li et al. 2003); hippocampus. Exercise induces the expression
therefore, IL-8 has been proposed to play a of FNDC5 not only in muscle, but also in hip-
role in skeletal muscle angiogenesis. However, pocampus, which leads to increased BDNF lev-
a recent study came to an opposite conclusion, els and neuroprotection in this region (Wrann
showing that elevated IL-8 secretion from hu- et al. 2013). This action can also be achieved by
man myotubes impairs capillary outgrowth elevation of circulating irisin levels. The exer-
(Amir et al. 2015). Besides the regulation of cise-induced release of cathepsin B (CTSB)
lipid metabolism, ANGPTL4 also regulates an- from skeletal muscle in mice was implicated in
giogenesis and vascular permeability (Baba- the improved memory function mediated by
poor-Farrokhran et al. 2015). Muscle-specific enhanced BDNF expression in the hippocam-
deficiency or overexpression of follistatin-like pus (Moon et al. 2016). This is supported by
1 (FSTL1) in mice reveals a beneficial effect on human data showing that exercise training in-
vascular repair processes (Miyabe et al. 2014). creases CTSB mRNA levels in muscle, as well as
systemic protein level, which is correlated with
cognitive functions (Moon et al. 2016).
Muscle –Bone Interactions
Muscle contraction influences bone mass dur-
Cancer Protection
ing development and growth, as well as bone
density, risk of fractures, and fracture healing Regular physical activity is recommended to re-
in adults. Mechanical stimuli are considered duce the risk for developing various tumors.
as driving forces in this relationship (Turner Cytokines derived from exercise-conditioned
2006), but there is also evidence that exercise- mouse serum or electrical stimulated muscle
induced muscle-derived factors regulate bone cells can inhibit cancer cell proliferation (Hoj-
formation and bone health. Myostatin inhibits man et al. 2011). The exercise-dependent mo-
bone repair, and consequently myostatin antag- bilization of natural killer cells plays a central
onists improve fracture healing (Hamrick et al. role in reducing tumor growth, and the myo-
2010). In contrast, IGF-1 (Doorn et al. 2013) kines IL-6 and IL-15 regulate maturation and
and secreted protein rich in cysteine (SPARC) redistribution of natural killer cells (Idorn and
have osteogenic properties and are positively Hojman 2016). Moreover, studies in mice sup-
associated with bone mineralization (Breen et port a role of exercise-induced SPARC in sup-
al. 2011; Pataquiva-Mateus et al. 2012). Bone pressing colon tumorigenesis by enhancing
mineral content is also increased by muscle-spe- apoptosis in colon cells (Aoi et al. 2013).
cific oversecretion of IL-15 (Quinn et al. 2009).
PHYSIOLOGICAL RELEVANCE OF
Improvement of Cognitive Function ENDOCRINE EFFECTS OF MYOKINES
Cognitive function can be improved and pre- The importance of exercise-induced myokines
served by regular physical activity (Duzel et al. in the regulation of immunomodulatory pro-
2016). An important factor in that regard is cesses, in angiogenesis, and in remodeling the
BDNF, which regulates synaptic plasticity, cell ECM in muscle is well established. Exercise-in-
survival, and differentiation in the brain duced myokines play a central role in orchestrat-
(Chao et al. 2006). Elevated systemic levels of ing the interaction of myofibers, immune cells,
BDNF following acute exercise are frequently fibroblasts, and endothelial cells (Fig. 1). In ad-
reported, but increases in BDNF mRNA and dition, the release of neurotrophic factors such
protein abundance in skeletal muscle are appar- as BNDF and neurotrophic factor-4 have been
ently not associated with a release of the protein proposed to be involved in promoting survival
(Matthews et al. 2009). However, in mouse and function of motoneurons (Nishimune et al.
2014). Thus, myokines are of crucial impor- whole-body knockout mice are less helpful in
tance for the adaptation of skeletal muscle to this context. There is the need for convincing
an increased physical workload. Moreover, as transgenic mouse models specifically targeting
described above, there are several exercise-regu- the exercise-regulated release of myokines from
lated muscle-derived factors with proposed skeletal muscle. This proved to be more chal-
endocrine effects (summarized in Fig. 2). The lenging than expected. Skeletal muscle – specific
biological effects attributed to myokines com- IL-6 knockout mice appear to have higher sys-
prise more or less all beneficial consequences of temic IL-6 levels following exercise (Gudiksen
regular physical activity. However, the extent to et al. 2016), which again shows the tight regu-
which endocrine effects of muscle-derived fac- lation and importance of feedback control
tors contribute to the health-promoting effects mechanisms in the cytokine network.
of exercise in humans is still unclear. First of all,
for many myokines, whether the increase in
transcript and protein abundance in muscle is FURTHER PERSPECTIVES
translated into increased systemic levels is un-
Role of the Extracellular Matrix in Exercise
certain. The studies of Steensberg provide evi-
Adaptations
dence that skeletal muscle accounts for a major
part of the systemic elevation in IL-6 following Structural proteins of the ECM are released by
exercise (Steensberg et al. 2000; Toft et al. 2011), their cellular sources within skeletal muscle and
but data for many other myokines is lacking. are highly abundant in the supernatant of cul-
Fibroblast growth factor 21 (FGF-21) has been tured skeletal muscle cells (Weigert et al. 2014).
classified as a myokine, because its expression Moreover, transcriptional and proteomics pro-
in skeletal muscle is increased several-fold in filing of the skeletal muscle following acute ex-
mouse models with mitochondrial disorders ercise and training revealed a large number of
(Kim et al. 2013a; Keipert et al. 2014). More- regulated ECM proteins, including several col-
over, serum levels of FGF-21 are elevated after lagens, proteoglycans, and modulators of the
acute exercise (Kim et al. 2013b). However, an- ECM such as cathepsins and matrix metallopro-
alyzing the flux of FGF-21 over the exercising teinases (Rullman et al. 2007; Norheim et al.
muscle and over the hepatosplanchnic bed in 2011; Heinemeier et al. 2013; Catoire et al.
humans reveals liver, rather than skeletal mus- 2014b; Hjorth et al. 2015; Hyldahl et al. 2015).
cle, is the main contributor to exercise-induced Although most of the regulated ECM com-
systemic increases in FGF-21 (Hansen et al. ponents may not have direct signaling proper-
2015a). Other myokines showed a pronounced ties, the importance of the dynamic nature of the
up-regulation following exercise in other or- ECM of skeletal muscle for mechanotransduc-
gans—for example, exercise also induces a tion, force transmission to tendons, protection
marked ANGPTL4 expression in liver (Kersten against force-induced injury, exercise-induced
et al. 2009)—and the contribution of skeletal angiogenesis, and ECM-residing progenitor
muscle to systemic ANGPTL4 levels following cells is well-acknowledged (Kjaer 2004; Gustafs-
exercise requires further clarification. son 2011). Notably, skeletal muscle insulin resis-
To elucidate the relevance of individual my- tance is accompanied by increased collagen con-
okines for a role in exercise adaptations, it tent (Berria et al. 2006) and decreased desmin
turned out to be a challenge to generate appro- and actinin-2 content (Hwang et al. 2010). Al-
priate animal models. Muscle-specific overex- terations in the ECM, such as the content of
pression of myokines in mice needs to be fine- hyaluronan, have been proposed to act as a phys-
tuned to yield a physiologically relevant local ical barrier and influence glucose and insulin
and systemic concentration and should ideally delivery (Kang et al. 2013; Williams et al.
mimic the transient changes. Because of the ex- 2015), whereas alterations in desmin or actinin
pression and release of most myokines from can influence mechanosignal transduction and
several tissues and their pleiotropic functions, translocation of glucose transporter-4 (Coletta
12
Adipose tissue
IL-6, ANGPTL4 → adipocytes
Lipolysis↑ Brain
IL-15, ANGPTL4 → endothelium
LPL activity ↓ Kynurenine↓
Irisin, BAIBA → adipocytes Stress/depression↓
Browning, thermogenesis↑
Meteorin-like → macrophages CSTB, irisin → BDNF
Cognitive function↑ Pancreas
Thermogenesis↑
Myostatin↓ IL-6 → β cells
Fat mass↓ Insulin secretion via GLP1
release
ANGPTL4, IL-6 → α cells

Hyperplasia
Liver GLP1
IL-6 → hepatocytes
Glucose metabolism
IL-10 → immune cells
Inflammation↓ Gut
IL-6 → L cells
Muscle
GLP1 release↑
Bone
Autocrine/paracrine effects Immune cells
IGF-1, SPARC, IL-15
(see Fig. 1)
Formation, mineralization↑ IL-10 → T cells
Myostatin↓ Inflammation↓
→ Healing↑ IL-1RA → IL-1α/β
Inflammation↓
CCL2 → monocyte
Cell attraction↑
Tumor
IL-6 → macrophages
IL-6, IL-15 → NK cells Alternative activation↑
Mobilization↑
SPARC → tumor cells
Apoptosis↑
Figure 2. Endocrine effects of exercise-regulated human myokines and metabolites. In addition to their autocrine and
paracrine effects, myokines act on adipose tissue, liver, gut, brain, pancreas, bone, circulating and resident immune cells,
and tumors. In most cases, exercise stimulates the release of myokines and metabolites (shown in black; BAIBA, b-amino
isobutyric acid). Notable exceptions are myostatin and kynurenine, which are reduced after regular exercise (shown in red).
(Figure created using illustrations provided by Servier Medical Art.)
and Mandarino 2011). Mutations in collagen eral mitochondrial key regulators and enzymes
VI lead to defective muscle microfibril forma- in primary human skeletal muscle cells and ac-
tion and mitochondrial dysfunction (Bushby et tivated TGF-b signaling may account for the
al. 2014; Zamurs et al. 2015). Furthermore, failure to enhance insulin sensitivity in some
ECM – integrin receptor interaction is involved subjects after training (Bohm et al. 2016). This
in diet-induced insulin resistance in mouse effect of TGF-b is not restricted to skeletal mus-
models (Kang et al. 2016). Another regulatory cle, because whole-body blockade of TGF-b sig-
level of signal transduction in skeletal muscle is naling in obese mice improves mitochondrial
the binding, release, and presentation of growth respiration in adipocytes, hepatic steatosis, glu-
factors such as VEGF and transforming growth cose tolerance, and energy homeostasis (Yadav
factor b (TGF-b) by the ECM (Hynes 2009), et al. 2011). Thus, TGF-b appears to be relevant
which can be directly influenced by the exer- not only for the ECM composition and inflam-
cise-dependent remodeling of the ECM. Thus, matory processes but also for improvements in
several modes of interaction exist between the glycemic control after exercise training.
ECM and myofibers within skeletal muscle
that can be involved in exercise-induced adap-
tations including improved metabolism and ex- FUTURE DIRECTIONS
ercise capacity.
Myometabokines
The secretome of skeletal muscle not only com-
TGF-b as Potential Regulator of Metabolic
prises proteins and peptides but also metabo-
Adaptations
lites and lipids. These factors can contribute to
The TGF-b protein family is of great impor- the health-promoting effects of exercise not
tance for muscle development and regeneration only caused by altered substrate fluxes between
(Kollias and McDermott 2008). TGF-b is an organs but also based on the potential of some
inhibitor of myogenic differentiation (Mas- metabolites and lipids to activate surface or in-
sague et al. 1986) and plays an important role tracellular receptors (Schoonjans et al. 1996;
in inflammatory process after muscle injury and Itoh et al. 2003; Hashimoto et al. 2007; Cao
fibrosis (Mann et al. 2011). After acute exercise et al. 2008). These factors can act as muscle-
or training, mRNA abundance of TGF-b1 and derived paracrine or endocrine factors and are
TGF-b receptor 2 is increased (Heinemeier et al. termed “myometabokines.” Metabolomics and
2013). Moreover, TGF-b signaling can be en- lipidomics analyses of arterial and venous plas-
hanced by release of active TGF-b protein ma samples of the exercising leg enable the iden-
from a large latent complex in the ECM by ex- tification of a wide range of metabolites and
ercise-activated metalloproteinases or mechan- lipids released from skeletal muscle (Xu et al.
ical force-mediated activation via integrin sig- 2016). In rodent studies, two interesting candi-
naling (Hynes 2009), but the contribution of dates with endocrine function have been iden-
these mechanisms to the enhanced TGF-b sig- tified. b-Amino isobutyric acid is released from
naling following exercise needs to be clarified. cultured muscle cells and increased in plasma of
Numerous TGF-b target transcripts, such as the exercising mice and trained humans. b-Amino
TGF-b inducible protein and other ECM pro- isobutyric acid contributes to the browning of
teins, are increased after exercise and training white fat and hepatic fat oxidation (Roberts
(Heinemeier et al. 2013; Neubauer et al. 2014). et al. 2014). Exercise training increases kynure-
Thus, TGF-b contributes to the adaptation of nine aminotransferase in skeletal muscle, in-
the ECM to exercise. Recently, TGF-b has also ducing a shift in circulating kynurenine to ky-
been implicated in the exercise-dependent reg- nurenic acid in both mice and humans, which is
ulation of PGC1a and substrate oxidation ca- proposed to be involved in the protection from
pacity of skeletal muscle (Tiano et al. 2015; stress-induced depressive disorders (Agudelo
Bohm et al. 2016). TGF-b1 down-regulates sev- et al. 2014; Schlittler et al. 2016).
MyomiRs In the case of myostatin with its clear func-

tion in regulating muscle mass and body fat
Other recently discovered components of the
content, a soluble form of the activin receptor
muscle’s secretome include regulatory, non-
type IIB, which blocks myostatin (Lee et al.
coding RNA molecules (micro-RNA [miRNA],
2016), was tested in a double-blind, placebo-
long noncoding RNA [lncRNA]) (Coenen-
controlled study in 48 healthy women and was
Stass et al. 2016). Exercise and training regu-
shown to increase total lean body mass and
lates the plasma miRNA profile in humans
muscle volume (Attie et al. 2013). Based on
(Baggish et al. 2011; Nielsen et al. 2014), which
the multiple potential beneficial effects of
differs from the miRNA signature in exercised
IL-6, current research is also focusing on the
or trained muscle (Nielsen et al. 2010; Russell
development of novel gp130 ligands. IL-6 and
et al. 2013). Muscle-enriched miRNA (referred
other cytokines share signaling via a gp130/a-
to as myomiRs) are involved in the regulation
receptor complex (Heinrich et al. 2003). Among
of myogenic processes and circulating miRNAs
them is CNTF, which has weight-lowering ef-
responding to exercise are associated with an-
fects in mice (Watt et al. 2006) and humans
giogenesis, inflammation, and mitochondrial
(Ettinger et al. 2003). The design of new
dynamics, and a role in the adaptation to ex-
gp130 ligands, by combining the beneficial
ercise is discussed (Russell and Lamon 2015).
signaling properties and abolishing the nega-
MyomiRs are also found in exosomes, interest-
tive effects, which in the case of IL-6 is trigger-
ing new players of the muscle’s secretome,
ing proinflammatory reactions, has been pro-
because they can carry a whole array of exer-
posed to be a promising future goal (Cron
cise-regulated factors, thereby transporting the
et al. 2016).
health-promoting information of exercise to
other tissues (Safdar et al. 2016).

CONCLUDING REMARKS
Based on the current state of knowledge, the
Therapeutic Potential of Exercise-Regulated
major physiological function of the secretory
Myokines
capability of skeletal muscle is to protect and
Although future research will provide more in- improve the functionality of the working mus-
sight into the relevance of endocrine effects of cle by regulating the intramuscular cross talk of
single myokines or other muscle-derived fac- myofibers, immune cells, fibroblasts, the vascu-
tors, the increasing knowledge about the bio- lature, and the bone. Furthermore, there is con-
logical function of exercise-regulated muscle- vincing evidence that factors secreted by skeletal
derived factors is a valuable source for novel muscle act as endocrine signaling mediators
therapeutic options to treat chronic diseases. and are involved in the beneficial effects of ex-
However, the transient regulation of most my- ercise on almost all cell types and organs. The
okines by exercise—a sharp increase in systemic entire secretome of exercising skeletal muscle
levels, followed by a decline within hours—is has not yet been described. Thus, novel compo-
a very important aspect when considering nents, including metabolites, lipids, and RNA
the therapeutic potential of myokines, because molecules, will add additional regulatory levels
chronically elevated systemic concentrations of to the interorgan cross talk. Because of the com-
most cytokines and ECM-regulating growth plexity of not only the muscle’s secretome, an
factors are associated with conditions of pro- “exercise mimetic” might not be possible, and
longed and uncontrolled inflammation and efforts to motivate people to increase their daily
are found in many diseases, including auto- physical activity should even be intensified. But
immune diseases, cancer, and obesity-related research has started to develop modified myo-
metabolic disorders, or muscular dystrophies kines that combine the beneficial effects and
(Akira et al. 1993; Gabay 2006; Hoene and Wei- omit the undesired side effects, aiming to sup-
gert 2008; Burks and Cohn 2011). port the treatment of chronic diseases.
ACKNOWLEDGMENTS games separated by a 72-h recovery. Scand J Med Sci

Sports 20: 740– 747.
C.W. acknowledges collaborators, in particular, Aoi W, Naito Y, Takagi T, Tanimura Y, Takanami Y, Kawai Y,
Peter Plomgaard and Bente Klarlund Pedersen, Sakuma K, Hang LP, Mizushima K, Hirai Y, et al. 2013. A
novel myokine, secreted protein acidic and rich in cyste-
The Centre of Inflammation and Metabolism ine (SPARC), suppresses colon tumorigenesis via regular
and the Centre for Physical Activity Research, exercise. Gut 62: 882– 889.
the Department of Infectious Diseases and Attane C, Foussal C, Le Gonidec S, Benani A, Daviaud D,
Community Regional Medical Center (CMRC), Wanecq E, Guzman-Ruiz R, Dray C, Bezaire V, Rancoule
C, et al. 2012. Apelin treatment increases complete fatty
Rigshospitalet, Copenhagen, Denmark, and acid oxidation, mitochondrial oxidative capacity, and
Stefan Lehr, Institute for Clinical Biochemistry biogenesis in muscle of insulin-resistant mice. Diabetes
and Pathobiochemistry, German Diabetes Cen- 61: 310– 320.
ter, Leibniz Center for Diabetes Research at the Attie KM, Borgstein NG, Yang Y, Condon CH, Wilson DM,
Pearsall AE, Kumar R, Willins DA, Seehra JS, Sherman
Heinrich Heine University Düsseldorf , Düssel- ML. 2013. A single ascending-dose study of muscle reg-
dorf, Germany, who contributed much to my ulator ACE-031 in healthy volunteers. Muscle Nerve 47:
understanding of myokines. The work of C.H. 416 –423.
Babapoor-Farrokhran S, Jee K, Puchner B, Hassan SJ, Xin X,
and C.W. is supported by a Grant (01GI0925) Rodrigues M, Kashiwabuchi F, Ma T, Hu K, Deshpande
from the German Federal Ministry of Education M, et al. 2015. Angiopoietin-like 4 is a potent angiogenic
and Research (BMBF) to the German Center for factor and a novel therapeutic target for patients with
proliferative diabetic retinopathy. Proc Natl Acad Sci
Diabetes Research (DZD e.V.) and by a Grant 112: E3030– E3039.
from the Leibniz Gemeinschaft (SAW-FBN- Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang
2013-3). F, Wang TJ, Chan SY. 2011. Dynamic regulation of circu-
lating microRNA during acute exhaustive exercise and
sustained aerobic exercise training. J Physiol 589: 3983–
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Skeletal Muscle as an Endocrine Organ: The Role of Myokines in

Exercise Adaptations
Christoph Hoffmann and Cora Weigert
Cold Spring Harb Perspect Med published online April 7, 2017
Subject Collection The Biology of Exercise
Theoretical and Biological Evaluation of the Link The Role of MicroRNAs in the Cardiac Response
between Low Exercise Capacity and Disease Risk to Exercise
Lauren Gerard Koch and Steven L. Britton Xiaojun Liu, Colin Platt and Anthony Rosenzweig
Skeletal Muscle as an Endocrine Organ: The Role Omics and Exercise: Global Approaches for
of Myokines in Exercise Adaptations Mapping Exercise Biological Networks
Christoph Hoffmann and Cora Weigert Nolan J. Hoffman
Rate Coding and the Control of Muscle Force Exercise and the Skeletal Muscle Epigenome
Roger M. Enoka and Jacques Duchateau Sean L. McGee and Ken R. Walder
Autophagy-Dependent Beneficial Effects of Role of Nuclear Receptors in Exercise-Induced
Exercise Muscle Adaptations
Jens Frey Halling and Henriette Pilegaard Barbara Kupr, Svenia Schnyder and Christoph
Handschin
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Skeletal Muscle as an Endocrine Organ: The Role

Christoph Hoffmann1 and Cora Weigert1,2,3

ity, suppression of tumor growth, and improvement of cognitive function. Muscle-derived

Editors: Juleen R. Zierath, Michael J. Joyner, and John A. Hawley

C. Hoffmann and C. Weigert

Myokines in Exercise Adaptations

Myokines in Exercise Adaptations

C. Hoffmann and C. Weigert

Immune cells Fibroblasts

Myokines in Exercise Adaptations

C. Hoffmann and C. Weigert

Myokines in Exercise Adaptations

et al. 2003), down-regulation of toll-like recep- Regulation of Myogenesis and Muscle

genic factors (Kanzleiter et al. 2014).

C. Hoffmann and C. Weigert

Myokines in Exercise Adaptations

ANGPTL4, IL-6 → α cells

(Figure created using illustrations provided by Servier Medical Art.)

Myokines in Exercise Adaptations

C. Hoffmann and C. Weigert

MyomiRs In the case of myostatin with its clear func-

other tissues (Safdar et al. 2016).

Myokines in Exercise Adaptations

ACKNOWLEDGMENTS games separated by a 72-h recovery. Scand J Med Sci

Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR,

C. Hoffmann and C. Weigert

Myokines in Exercise Adaptations

Kundgen A, Suckau D, Germing U, Czibere A, Lehr S.

C. Hoffmann and C. Weigert

and involved in muscle hypertrophy. Biochem Biophys Res

Myokines in Exercise Adaptations

C. Hoffmann and C. Weigert

Myokines in Exercise Adaptations

C. Hoffmann and C. Weigert

Skeletal Muscle as an Endocrine Organ: The Role of Myokines in

Cold Spring Harb Perspect Med published online April 7, 2017

Subject Collection The Biology of Exercise

For additional articles in this collection, see http://perspectivesinmedicine.cshlp.org/cgi/collection/

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