Postmitotic Expression of SOD1G93AGene Affects the Identity of Myogenic Cells and Inhibits Myoblasts Differentiation

Abstract

To determine the role of mutant SOD1 gene (SOD1G93A) on muscle cell differentiation, we derived C2C12 muscle cell lines carrying a stably transfected SOD1G93Agene under the control of a myosin light chain (MLC) promoter-enhancer cassette. Expression of MLC/SOD1G93Ain C2C12 cells resulted in dramatic inhibition of myoblast differentiation. Transfected SOD1G93Agene expression in postmitotic skeletal myocytes downregulated the expression of relevant markers of committed and differentiated myoblasts such as MyoD, Myogenin, MRF4, and the muscle specific miRNA expression. The inhibitory effects of SOD1G93Agene on myogenic program perturbed Akt/p70 and MAPK signaling pathways which promote differentiation cascade. Of note, the inhibition of the myogenic program, by transfected SOD1G93Agene expression, impinged also the identity of myogenic cells. Expression of MLC/SOD1G93Ain C2C12 myogenic cells promoted a fibro-adipogenic progenitors (FAPs) phenotype, upregulating HDAC4 protein and preventing the myogenic commitment complex BAF60C-SWI/SNF. We thus identified potential molecular mediators of the inhibitory effects of SOD1G93Aon myogenic program and disclosed potential signaling, activated by SOD1G93A, that affect the identity of the myogenic cell population.