## 4 Skeletal Muscle Regeneration and Histone Modifications  
Skeletal muscle has an excellent ability to regenerate after injury. Satellite cells, a postnatal source for the growth and regeneration of skeletal muscles, differentiate into muscle fibers following their proliferation and fusion, and/or incorporation into resident fibers [34; 35]. Satellite cells in adult skeletal muscle are mitotically quiescent and express the paired-box transcription factor Pax7 [36]. Quiescent satellite cells become active in response to muscle injury. Upregulation of MyoD and myogenin expression in active satellite cells leads to the myogenic differentiation. A minority population downregulates MyoD, maintains Pax7, and returns to a quiescent state for self-renewal [37]. As the total number of satellite cells in adult muscles remains relatively constant following repeated muscle injury, the satellite cell population must be carefully maintained throughout the life. Histone modifications play a critical role in the self-renewal of satellite cells as well as their ability to regenerate skeletal muscle fibers. Lysine-specific demethylase 1 (LSD1) is an epigenetic enzyme involved in transcriptional repression or activation of genes through the demethylation of mono- and di-methylated histone H3K4 [38; 39]. [PERSON] et al. [40] have reported that satellite-cell-specific LSD1 knockout mice exhibited severe failure in muscle regeneration after injury. Surprisingly, loss of LSD1 in satellite cells promoted the differentiation into brown adipocytes. The researchers also confirmed this phenomenon in vitro using C2C12 myoblasts, in which H3K4 me2 levels were significantly decreased at the locus of the pro-adipogenic factor Gli81, thereby enhancing the gene expression during muscle regeneration. [PERSON] et al. [32] demonstrated that SUV4-20H1, an H4K20 dimethyl transferase, controlled satellite cell quiescence by promoting the formation of facultative heterochromatin. Satellite-cell-specific SUV4-20H1 knockout mice exhibited decreased levels of H3K27 me3 and H4K20 me2 in the satellite cells, which triggered MyoD expression in these cells during muscle regeneration; loss of Pax7-positive quiescent satellite cells resulted in the severe failure of muscle regeneration. These observations indicated that histone modifications are necessary for fine tuning of gene expression that maintains the lineage and quiescence of muscle stem cells. Canonical histones H3.1 and H3.2, and noncanonical histone H3.3 are incorporated into distinct loci and differentially function in association with unique histone modifications. H3.3 is exchanged with canonical histones at transcriptionally active loci, whereas it is also enriched at pericentric heterochromatin and telomeres in which the gene transcription is silenced [41]. It is known that transcription-activating H3K4 me3 is prevalent in H3.1 and H3.2, whereas H3.3 is preferably modified by transcription-repressing H3K27 me3 [42]. Figure 4: **Overview of exercise-induced histone turnover. ** Tetracycline-inducible H2B-GFP expression model demonstrated the histone turnover in skeletal muscle fibers [30]. Since the histone turnover is referred to as the exchange of histone components with new histones, the incorporation of induced H2B-GFP into nucleosomes indicates the turnover of histone H2B. Upregulation of myonuclear facilitates chromatin transcription (FACT), and histone remodelers, such as H3.3, H3K27 me3, and H4K20 me2, were associated with the activation of histone turnover, which drastically enhanced the gene response to a single bout of exercise. [PERSON] et al. [43] reported that the incorporation of H3.3 into skeletal muscle gene loci was indispensable for the gene expression induced during myogenesis, suggesting that such incorporation potentiated the transcription of specific loci.