Mechanism of Satellite Cell Regulation by Myokines

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J Phys Fitness Sports Med, 6 (5): 311-316 (2017) DOI: 10.7600/jpfsm.6.311 JPFSM: Review Article Mechanism of satellite cell regulation by myokines

Yasuro Furuichi* and Nobuharu L. Fujii

Department of Health Promotion Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji, Tokyo 193-0397, Japan

Received: July 19, 2017 / Accepted: August 7, 2017 Abstract Skeletal muscle stem cells, known as satellite cells, participate in postnatal skeletal muscle growth, regeneration, and hypertrophy. They are quiescent in the resting state, but are activated after muscle injury, and subsequently replicate and fuse into existing myofibers. The behavior of satellite cells during muscle regeneration is regulated by extrinsic factors, such as the extracellular matrix, mechanical stimuli, and soluble factors. Myokines, muscle-derived secretory factors, are important regulators of satellite cell activation, proliferation, and differentiation. It is well known that muscle injury induces the release of various growth factors from myofibers, and these growth factors affect satellite cells. It has recently been shown that myokines secreted from myofibers without cell damage also regulate satellite cell functions. Here, we summarize myokines with known roles in the regulation of satellite cells and the mechanism underlying this regulatory process. Keywords : secretion, myogenesis, muscle regeneration

regulation, but there are also molecules related to muscle Introduction regeneration or plasticity. In this review, we introduce the Skeletal muscle is a unique tissue that has a remarkable reported myokines involved in the regulation of satellite ability to regenerate after injury. In response to tissue cell behavior and its molecular mechanism. damage, muscle stem cells, known as satellite cells, initi- ate the myogenic program and repair damaged myofibers Definition of a myokine or form new myofibers. Satellite cells reside between the sarcolemma and basal lamina of myofibers1) and, upon ac- The term “myokine” is composed of myo (which means tivation, proliferate and differentiate to myofibers. Satel- “muscle”) and kine (which means “movement”). Peder- lite cells are heterogeneous, and a portion of satellite cells sen et al. have defined myokines as “cytokines and other divide asymmetrically to produce myogenic progenitors peptides that are produced, expressed, and released by or symmetrically to maintain the stem cell pool. The abil- muscle fibers and exert either paracrine or endocrine ef- ity of satellite cells to suitably balance quiescence, self- fects”2). We have suggested that not only proteins or pep- renewal, and commitment is important for skeletal muscle tides, but also lipids, amino acids, and metabolites serving homeostasis. as ligands by binding to receptors on the cell membrane Recent studies have revealed that the regulation of sat- surface should be categorized as myokines. Furthermore, ellite cells is governed by intrinsic factors, but also by since there is evidence indicating that microRNAs are extrinsic factors, such as the extracellular matrix (ECM), released from skeletal muscle during exercise3,4), nucleo- mechanical stimuli, and soluble factors. Myofiber-derived tides, such as small RNAs, also fall into the category of proteins are well-known regulators of satellite cell func- myokines. tion. Proteins leak from skeletal muscle cells when the Several studies have shown that satellite cells and un- skeletal muscle is damaged, and these proteins act on differentiated myoblasts also secrete various proteins, and satellite cells located right beside muscle fibers. Recently, these molecules regulate muscle regeneration in a para- skeletal muscle has been considered a secretory organ that crine manner (details are described below). Until now, produces bioactive proteins, termed myokines, which are myokines have been unambiguously recognized as mol- released in the absence of cell damage. Myokines are se- ecules derived from myofibers, which are matured muscle creted in response to exercise (muscle contraction), but it cells. Since satellite cells and myoblasts are included is also well known that most myokines are constitutively in muscles in a broad sense, they might be classified as secreted from skeletal muscle cells. Many myokines are myokines. involved in anti-inflammation and systematic metabolic The myokine concept has been developed recently, but it was previously recognized that several bioactive *Correspondence: [email protected] molecules are released from skeletal muscles following 312 JPFSM: Furuichi Y and Fujii NL

injury and act on surrounding cells in a paracrine man- tion8,9). Soluble factors secreted from skeletal muscle cells ner. In 1986, Bischoff examined the satellite cell prolif- (myokines) are also important regulators of satellite cell eration rate in medium containing intact muscle extract functions. In this section, we introduce myokines known or crushed muscle extract5). The mitogenic activity was to influence satellite cell behavior. stimulated by the direct addition of crushed muscle extract, suggesting that soluble molecules are released from Myokines involved in satellite cell activation damaged muscles and induce cell proliferation5). Mes- senger proteins conveying to satellite cells that myofibers Once muscle fibers are injured, cytokines and chemo- suffered damage are released from damaged fibers, and kines are first secreted from macrophages that migrate they correspond to currently defined myokines. to the injured site. Growth factors are also released from damaged muscle fibers, which act on satellite cells and cause muscle regeneration. Released growth factors are Functional regulation of satellite cells by myokines important for activating and inducing the proliferation of Satellite cells are typically quiescent in adult muscles, satellite cells10). but can be activated, proliferate, and fuse into nascent IGF-1 (Insulin-like growth factor-1) is a hormone mainly myotubes or existing muscle fibers. In vitro studies have produced in the liver and is secreted into circulating blood shown that satellite cells are able to divide asymmetrically in response to other growth factors. IGF-1 expression has to generate myogenic progenitors or to divide symmetri- also been confirmed in skeletal muscle and is released cally to maintain the satellite cell pool. Satellite cell fate from skeletal muscle cells by factors that induce cell mem- is governed by a variety of extrinsic factors. For example, brane damage, such as stretching, overloading, or vigorous stromal cells and nerve-muscle junctions in skeletal mus- contraction11). IGF-1 derived from skeletal muscle acts cle tissue secrete cytokines and regulate the cell cycle and on satellite cells in a paracrine manner and contributes to gene expression in satellite cells6). In addition, the basal muscle hypertrophy12). IGF-1 secreted from myofibers in lamina, composed of an ECM network, is also important response to injury binds to the specific receptor IGFR-1 of because ECM molecules function as the receptors of sat- satellite cells and promotes proliferation and differentia- ellite cells, and the elasticity of the ECM regulates satel- tion via Ras-ERK (Extracellular signal-regulated kinase) Figure 1 lite cell function7). Furthermore, bioactive molecules in and IRS-PI3 signaling13,14). circulation also affect satellite cell function because blood FGF-2 (Fibroblast growth factor 2) is a growth factor exchange between heterogeneous individuals (parabiosis) expressed in skeletal muscle and released in response drastically changes the potential of muscle regenera- to cell membrane damage15). FGF-2 is known to act as a regulator of cell proliferation and differentiation via the activation of MAPK (Mitogen-activated protein kinase) signaling. The p38α/β MAPKs, which are activated in 30 response to FGF-2, are required for satellite cells to enter the cell cycle from a quiescent state16). Additionally, FGF- 25 2 is essential for the G1 to S phase of the cell cycle by activating ERK1/2 signaling in proliferating myoblasts17), 20 suggesting that FGF-2 acts as a messenger in the initial stage of myogenesis after muscle injury. Taken together, 15 in the process of muscle regeneration by satellite cells after injury, myokines released from damaged muscle fibers

Satellite Cells Satellite 10 act as messengers. (Cell number/fiber)

5 Myokines enhance the proliferation and differentiation of satellite cells 0 IL-15 (Interleukin-15) is a cytokine that is highly ex- Intact Crushed Basal muscle muscle pressed in the skeletal muscle; it acts on adipose tissue medium extract extract in an endocrine manner and is recognized as an exercise- induced secretory myokine that regulates energy metabo- Fig. 1 Effect of muscle extraction on satellite cell prolifera- lism in the whole body. On the other hand, it has been tion (modified from Bischoff 5)). demonstrated that IL-15 increases protein synthesis, in- Isolated muscle fibers were cultured for 48 h in basal hibits protein degradation, and is involved in muscle hy- medium containing 1 mg/ml crushed muscle extract or pertrophy18,19). According to one study, IL-15 stimulated intact muscle extract. Satellite cells labeled with [3H] thymidine were counted. Crushed muscle extract en- muscle cell differentiation based on cell culture experi- 20) hanced satellite cell proliferation. ments . Figure 2

JPFSM: Myokines and satellite cells 313

Distant Myofiber Nearby Myofiber Injured Myofiber

Secretion Secretion Leakage Circulation Myokines IGF-1 FGF-2 FGF-2 Myostatin IGF-1 IL-6 LIF GDF11 IL-15

ActivationA ti & Fusionon & Self-renewal Proliferation Differentiation Satellite Cell

Fig. 2 Myokines regulate satellite cell behavior. Myokines are secreted from myofibers and released from injured myofibers. They regulate the activation, proliferation, differentiation, and self-renewal of satellite cells. FGF-2: fibroblast growth factor-2, IL-6: interleukin-6, IGF-1: insulin-like growth factor-1, LIF: leukemia inhibitory factor, GDF-11: growth differentiation factor-11, IL-15: interleukin-15.

LIF (Leukemia inhibitory factor) is a cytokine identi- vents the loss of quiescence, a decrease in satellite cells, fied as a proliferation inhibitor in leukemic cells, but is and impaired muscle regeneration26). also known as a myokine secreted from skeletal muscle IL-6 (Interleukin-6), an inflammatory cytokine, is an cells21). Muscle-derived LIF is supposed to function in aging factor whose blood level increases during aging; it skeletal muscle hypertrophy via the activation of satellite has been suggested to be associated with skeletal muscle cells. Spangenburg et al. showed that skeletal muscle hy- atrophy27). The JAK-STAT pathway downstream of the pertrophy due to overload does not occur in LIF knockout IL-6 receptor is also activated by aging, which reduces mice, but is rescued by the administration of LIF22). It has the self-replicating ability of satellite cells. Inhibition of also been shown that LIF stimulates satellite cell prolif- this pathway rescued the decreased number of quiescent eration and represses myogenic differentiation via the sig- satellite cells and impaired muscle regenerating ability27). naling pathways of JAK1, STAT1, and STAT323,24). These IL-6 is the most popular myokine, but its physiological studies suggest that LIF is an exercise-induced myokine functions are diverse, including whole body metabo- that activates satellite cell proliferation in a paracrine lism28). Acute exercise increases IL-6 levels in plasma, manner. while chronic exercise decreases IL-6 levels in the resting state29). Exercise training effectively improves the skeletal muscle regeneration ability30), but detailed studies on the Myokines that regulate the self-renewal of satellite cells contribution of myokines, such as IL-6, are needed. The self-renewal of satellite cells is a necessary process to prevent depletion. It has been reported that the num- Myokines that negatively regulate satellite cell function ber of satellite cells decreases during aging25), and this is thought to be due to a reduced self-renewal capacity. Myostatin, formerly known as GDF (growth differentia- FGF-2, which is an activator of satellite cells, negatively tion factor)-8, is a member of the TGF-β superfamily and regulates self-renewal26). In aged mice, the expression of is recognized as a myokine that regulates muscle size31,32). FGF-2 in muscle fibers is upregulated, and FGF signaling Similar to other members of the TGF-β superfamily, myo- in satellite cells is increased. A reduction in FGF activity statin activates the canonical Smad2/3 signaling pathway, by the inhibition of FGF signaling in satellite cells pre- via identical activin type II receptors, and regulates the 314 JPFSM: Furuichi Y and Fujii NL expression of genes involved in myogenesis. In a cell well as myoblast proliferation, and inhibits muscle dif- culture experiment using C2C12 myoblasts, myostatin ferentiation via the cell surface receptor c-Met43-45). Rodg- caused an increase in the expression of p21, an inhibitor ers et al. have recently shown that muscle injury on the of Cyclin-dependent kinase (Cdk), and the suppression unilateral limb of mice affects distant satellite cells in the of Cdk2 activity, resulting in the inhibition of cell prolif- uninjured contralateral leg, suggesting that injury-induced eration33). It has been shown that myostatin inhibits the soluble molecules affect satellite cells via the blood- activation of satellite cells and also negatively regulates stream. Rodgers explained that the activation of opposite the self-renewal of satellite cells34). Furthermore, myo- satellite cells is induced by HGF, which is released from statin inhibits myoblast differentiation by suppressing the injured leg and activates mTOR (mammalian target MyoD via Smad3 signaling. Since myostatin is crucial for of rapamycin) signaling46). Semaphorin 3A (Sema3A), a proliferation and differentiation in satellite cells, it can be class 3 vertebrate-secreted semaphorin, is also a satellite applied to the treatment of muscle weakness or muscle cell-derived secretory protein. The expression of Sema3A dystrophy by suppressing myostatin function35). is up-regulated at the early-phase of muscle differentia- GDF-11, another TGF-β superfamily protein, is closely tion during muscle regeneration in vivo47). Recently, it related to myostatin, sharing 89% sequence homology36). has been shown that the deletion of Sema3A decreases GDF-11 is reported to act on skeletal muscle mass and is slow-type muscle fibers in cultured cells and transgenic related to aging, but its effects are controversial. GDF- mice, suggesting that Sema3A is a novel factor for slow- 11 was identified as a rejuvenating factor for skeletal myofiber commitment48). muscle because GDF-11 levels decreased with aging Satellite cells interact with the surrounding extracel- and restoring GDF-11 levels reversed the impairment lular environment, including fibroblasts. Recently, it has of skeletal muscle function37). However, several stud- been demonstrated that activated satellite cells secrete ies do not support the rejuvenative influence of GDF-11 exosomes containing microRNAs that regulate fibroblast on dysfunction in aged skeletal muscle. Egerman et al. collagen expression49). miRNA-206 was identified as a claimed that the original reagent used to measure GDF- suppressor of RRBP1 that regulates collagen synthesis in 11 also detects other molecules, including myostatin, and fibroblasts. These findings revealed that satellite cells in- showed that GDF-11 actually increases with aging; and, teract with neighboring myoblasts or non-muscle cells via in fact, has deleterious effects on skeletal muscle regen- muscle-derived secretory molecules. eration38). Additionally, it has been shown that GDF-11 decreases satellite cell proliferation in vitro39), suggesting Concluding remarks that GDF-11 has a negative effect on muscle regeneration, in agreement with Egerman et al. The discrepancy in Myokine research is in the early stages, but new myo- the age-related changes of GDF levels can be explained kines are still being discovered. The identification of nov- by methodological issues with respect to detection owing el myokines related to the regulation of the quality and to the high similarity between myostatin and GDF-11. quantity of skeletal muscle and the elucidation of underly- The original group who reported age-related decreases ing mechanisms can lead to the prevention and treatment in GDF-11 have published corroborative results using of skeletal muscle diseases, such as sarcopenia. In fact, antibody-based methods, but they no longer distinguish Follistatin and GASP (GDF-associated serum protein) are between GDF-11 and myostatin40). However, another candidate therapeutic molecules for muscle diseases50). group has recently overcome these methodological chal- Recently, the muscle contraction system of cultured cells lenges for the quantification of GDF-11 by developing an has been established, enabling the discovery of novel LC-MS/MS assay, and showed that GDF-11 levels do not myokines secreted by muscle contraction51). It is expected decrease as age increases41). Taken together, the decrease that exercise-induced health benefits might be explained in GDF-11 during aging and its application as a potential by the myokine hypothesis. Further studies are needed to target to reverse muscle dysfunction are not supported by clarify the mechanisms underlying such benefits. published studies to date. Conflict of Interests Molecules secreted from satellite cells The authors declare that there is no conflict of interests After muscle injury, not only myofibers, but also satel- regarding the publication of this article. lite cells secrete soluble factors and contribute to muscle regeneration by regulating the expansion or differentiation of surrounding satellite cells. HGF (hepatocyte Acknowledgments growth factor) is mainly expressed in mesenchymal cells, This review was supported by a Grant-in-Aid for JSPS Fellows 42,43) but is also expressed in satellite cells and acts directly (# 24-173, YF) from the Japanese Ministry of Education, Science, in an autocrine manner. Released HGF induces the satel- Sports and Culture, and Funding Program for Next Generation lite cell entry from the quiescent state to the cell cycle as World-Leading Researchers LS102 to NLF. JPFSM: Myokines and satellite cells 315

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