Activation and nuclear translocation of PKCε promotes skeletal muscle cell differentiation via HMGA1 downregulation

Abstract

The role of novel PKCs in skeletal muscle differentiation has recently emerged. PKCθ is the most expressed isoform of PKCs in muscle and it promotes the fusion of myoblasts [1]. Recently, we have demonstrated that PKCε is implicated in myocardiocyte differentiation of bone marrow mesenchymal stem cells [2] but the role of PKCε in skeletal muscle cell regeneration has only recently emerged [3]. We here demonstrate that both nuclear and cytoplasmic fractions of PKCε are up-regulated during in vitro C2C12 cell line and satellite cell differentiation. We also show that PKCε is able to modulate myogenic differentiation genes via a downmodulation of HMGA1 proteins that promotes myogenin accumulation and mature myoblast formation. To study the effects of PKCε on muscle regeneration, we have used the in vivo model of CTX-induced skeletal muscle injury. We show that the upregulation of PKCε also occurs in vivo, particularly in the centro-nucleated regenerating fibers that are derived from the fusion process of the resident satellite cells, suggesting a role for PKCε in human satellite cell-driven muscle repair and substitution, with clinically relevant implications in human muscle pathology.