HDACs in Skeletal Muscle Regeneration

Skeletal muscle has the capability to regenerate, but like other tissues, its regenerative capacity is limited. Skeletal muscle regeneration and repair can be divided into three, sometimes overlapping, phases: (1) inflammation, (2) tissue formation, and (3) tissue remodeling [reviewed in Grefte et al. (2007)]. Upon myofiber injury, damage to the plasma membrane causes a large influx of extracellular calcium, resulting in calcium-dependent proteolysis (Alderton and Steinhardt 2000). Myofiber necrosis ensues and inflammatory cytokines are released from myofibers as well as from nearby inflammatory cells. These cytokines attract neutrophils and later macrophages that engulf and digest cellular debris. Growth factors and cytokines released from the site of injury activate a distinct population of progenitor cells, called satellite cells, which are located between the sarco-lemma and the basement membrane of myofibers. Satellite cells proliferate and differentiate into myoblasts. Satellite cell differentiation is similar to embryonic myogenesis in that it requires a specific milieu of transcription factors, most importantly myogenic regulatory factors (MRFs). Eventually, these activated satellite cells fuse to each other or existing myofibers, thus forming new muscle tissue. Interestingly, tissue macrophages are required for satellite cell proliferation and muscle cell regeneration (Camargo et al. 2003). The final stage of muscle regeneration and repair is tissue remodeling, which involves maturation of differentiated satellite cells. Shortly after fusion of the myoblasts, the myofibers are rather small with centrally located nuclei (Hawke and Garry 2001). Maturation involves migration of the nuclei to the periphery and hypertrophy of the myofiber.

A few studies have suggested that HDACs may play a role in muscle regeneration and satellite cell activation. TIS7 is a transcriptional corepressor important to muscle cell regeneration. TIS7-null mice display a delay in injury-induced muscle regeneration and reduced expression of MRFs, MyoD and myogenin, despite normal muscle development (Vadivelu et al. 2004). Apparently, the satellite cells of TIS7-null mice have a decreased capacity for differentiation. TIS7 transcriptional repression is HDAC-dependent, requiring HDAC1 and possibly HDAC4 as well (Vietor et al. 2005). Conversely, HDAC inhibitors (HDACIs) have proven therapeutically useful in treating mouse models of muscular dystrophies by enhancing muscle regeneration (Colussi et al. 2008; Minetti et al. 2006). The beneficial effects of HDACIs in the treatment of muscular dystrophy are derived from their influence upon the follistatin-myostatin pathway (Iezzi et al. 2004). Myostatin belongs to the TGF-p family and negatively regulates myofiber size (Lee and McPherron 2001). Myostatin antagonist, follistatin, is activated upon muscle injury, recruits myoblasts, and promotes myoblast fusion (Iezzi et al. 2004). HDACIs act by upregulating follistatin thereby stimulating myoblast recruitment and fusion, and hence muscle regeneration. Furthermore, in mouse models of Duchenne muscular dystrophy (DMD), skeletal muscle has elevated levels of class I HDACs. Blockade of class I HDACs, specifically HDAC2, successfully abates disease progression (Colussi et al. 2008). Whether class IIa HDACs are involved in skeletal muscle regeneration is not known.

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