Physical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure [1]. Exercise is a subset of physical activity that is planned, structured, and repetitive [1] and exerts many beneficial effects on the body across species [2,3]. Exercise is a key factor in the prevention and treatment of metabolic diseases. It has also been demonstrated that exercise provides protection from stress-induced depression via induction of the expression of kynurenine aminotransferases [4]. In addition, exercise exerts anti-tumor effects [5,6]. These beneficial effects are considered to be provided by myokines, also called exerkines, that are released from multinuclear cells, myofibers, composing skeletal muscle [4,5]. Recent studies of potential exerkines or exercise-dependent factors are briefly summarized in Table 1 [4-10]. Myofiber itself, including the component of myosin heavy chain isoform, extracellular remodeling, and the number of nuclei in myofibers are affected by exercise [11]. As the amount of circulating exerkines is limited, for identifying new exerkines, it is critical to know the cellular network and the direct effects of mechanical cues on skeletal muscle loaded by exercise. In addition to myofibers, skeletal muscle contains muscle satellite cells (MuSCs), endothelial cells, and mesenchymal progenitor cells (also called fibro/adipogenic progenitors [FAPs]) [12]; MuSCs play critical roles in muscle hypertrophy induced by mechanical loading. Here, we review the behaviors of MuSCs in skeletal muscle loaded by exercise or resistance training in mouse models.

A characteristic feature of muscle hypertrophy induced by mechanical loading is an increase in myofiber size, thus requiring an increase in protein synthesis. Another feature is an increase in the number of myonuclei. Since there is a limit to the cytoplasmic area that can be dominated by a single nucleus of a myofiber, new myonuclei must be generated to maintain a constant cytoplasmic area; this is known as the myonuclear domain theory. It is also considered that the number of myonuclei must increase to supply ribosomes that are the rate-limiting factor for protein synthesis. Since only MuSCs can supply nuclei to myofibers, MuSCs are generally considered essential for muscle hypertrophy. However, the debate on whether MuSC was necessary for hypertrophy occurred in 2007 [60]. At that time, methodological issues remained. Ten years later, the same debate recurred with two different reports using genetically modified MuSC-depleted mice [61,62]. As O’Connor and Pavlath [60] stated, short-term hypertrophy may not require an increase in the number of myonuclei, but no conclusion can be reached without a long-term experiment. To the best of our knowledge, all research groups observed blunted muscle hypertrophy at least in long-term experiments when myonuclear accretion was impaired [42,63]. Accumulating evidence also suggests the critical role of myonuclear accretion by MuSCs in both exercise and resistance training animal models [64-67]. Thus, it can be concluded that MuSCs are necessary for muscle hypertrophy induced by mechanical loading [41].

A recent study has shown that, in developing myofibers, there is some tolerance to the transcriptional capacity of myonuclei. In myofibers with approximately half of the nuclei, the transcriptional capacity of total RNA in one nucleus is doubled [68]. However, interestingly, the reserve capacity is reduced in myofibers harboring 75% of myonuclei; thus, the myofiber size was similarly reduced to that of the myofibers with half the nuclei [68]. It has also been demonstrated that the number of myonuclei defines the size of myofibers in both humans and mice [69]. These studies also indicate the critical roles of myonuclear number and MuSCs, because MuSC is also responsible for the increase in myonuclear number during the developmental stage [70].

In a muscle mechanically loaded by exercise or resistance training, MuSCs start to proliferate and eventually supply new myonuclei that are critical for efficient muscle hypertrophy. MuSCs in loaded muscles proliferate by mechanisms different from those in regenerating muscle, one of which is a sustained expression of HeyL. As myonuclei number, and perhaps also the quality, directly influence the myofiber size, MuSC-mediated control of these parameters might be an innovative therapeutic approach for muscular disorders, including sarcopenia. Elucidation of the molecular mechanisms underlying the MuSC activation and proliferation and the related cellular network will lead to the discovery of new aspects of skeletal muscles as an endocrine organ.