The discovery of a new role of HDAC8 in skeletal muscle differentiation and in centronuclear myopathy insurgence

Histone Deacetylase 8 (HDAC8) is a member of class I HDACs with peculiar characteristics: it is subjected to posttranslational phosphorylation and presents differences in substrate specificity, suggesting a unique role for HDAC8 across the HDACs family. For example, HDAC8 activity is specifically inhibited by molecules such as PCI-34051, with a 200-fold higher selectivity than other HDACs. Here, we describe for the first time a specific expression for HDAC8 during skeletal muscle differentiation. In C2C12 myoblasts the expression of HDAC8 increases during differentiation and in RD/18 and RD/12 rhabdomyosarcoma cells, respectively with low and high tumorigenic potential consistent with their differentiating capability, its expression correlates with the differentiation degree. Furthermore, we demonstrate that PCI-34051-mediated-HDAC8-inhibition impairs myogenesis in C2C12 myoblasts and in zebrafish embryos. In zebrafish, when HDAC8 activity is inhibited, only type I fibres are reduced. Moreover, preliminary data show altered expression of HDAC8 in muscle derived from centronuclear myopathy (CNM) affected patients in comparison with healthy donors. CNM is a condition characterized by skeletal muscles weakness, hypotonia and atrophy mainly in type 1 fibres. Mutations in MTM1, DNM2, BIN1, RYR1 or TTN genes have been associated with CNM, although some patients do not carry mutations in these genes. Hence the need to identify additional genes associated with CNM. In this work, we demonstrate a new role for HDAC8 activity in normal skeletal muscle differentiation, in rhabdomyosarcoma and we suggest a potential involvement of HDAC8 in CNM insurgence