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 differen- tiation. 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 myo- kines 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 mecha- nism 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 ex- tract, 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 af- ter injury, myokines released from damaged muscle fibers Satellite Cells Satellite 10 act as messengers. (Cell number/fiber) 5 Myokines enhance the proliferation and differentia- tion 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