Inhibiting histone acetyltransferase activity rescues differentiation of emerin-null myogenic progenitors

Emery-Dreifuss Muscular Dystrophy (EDMD) is a disease characterized by skeletal muscle wasting, contractures of the major tendons, and cardiac conduction defects. Compromised skeletal muscle regeneration is predicted to result from impaired muscle stem cell differentiation. Mutations in the gene encoding emerin cause EDMD. We previously showed emerin-null myogenic progenitors fail to properly exit the cell cycle, fail to exhibit decreased myosin heavy chain (MyHC) expression and have decreased myotube formation. Treatments with theophylline, a HDAC3 activator, rescued myotube formation in differentiating emerin-null myogenic progenitors, suggesting emerin activation of HDAC3 activity is important for myogenic differentiation. Pharmacological inhibitors of H4K5 histone acetyltransferases (HATs) were used to test if the deacetylation function of HDAC3 by theophylline treatment was responsible for rescuing emerin-null myogenic differentiation. Nu9056 and L002 were added to differentiating wildtype and emerin-null myogenic progenitors and differentiation was assessed. HAT inhibition rescued emerin-null myogenic progenitor differentiation. In contrast to treatment with these HAT inhibitors, emerin-null myogenic progenitors treated with SRT1720, which targets SIRT1, a NAD+-dependent deacetylase, showed no significant change in myotube formation. Thus, we conclude emerin regulation of HDAC3 activity is important for myogenic differentiation. Therefore, pharmacological targeting of H4K5 acetylation is a promising therapeutic approach for rescuing muscle regeneration in EDMD.