RCOR1 promotes myoblast differentiation and muscle regeneration

Abstract

RCOR proteins belong to a family of highly conserved transcription corepressors (RCOR1, RCOR2 and RCOR3) that regulate the activity of associated histone demethylase 1 (LSD1) and histone deacetylase 1/2 (HDAC 1/2) in chromatin-modifying complexes. Despite the described function of LSD1 in skeletal muscle differentiation and regeneration, the role of RCOR family in myogenesis remains unknown. We found that RCOR1 is highly expressed in proliferating myoblasts and activated satellite cells, but not in mature myofibers during postnatal growth and regeneration of skeletal muscle. Knockdown of RCOR1 impaired myoblast differentiation and fusion by inhibiting the expression of the key myogenic regulatory factor myogenin. Moreover, RCOR1 depletion impaired myoblast proliferation through increasing the expression of cell cycle inhibitor p21. Consistently, in a mouse model of skeletal muscle injury, depletion of RCOR1 supressed satellite cell activation and differentiation which resulted in impaired muscle regeneration. RCOR1 was found physically associated with LSD1 and myogenic regulatory factor MyoD and contributed to LSD1 stability in myoblasts. As for other RCOR family members, RCOR2 had no effect on myoblast differentiation while the loss of RCOR3 increased myoblast proliferation leading to supressed expression of myogenic markers MyoD and myogenin and impaired myoblast differentiation. However, germline deletion of RCOR3 (RCOR3-/-) did not affect muscle phenotype, suggesting a possible functional redundancy among RCOR family members during muscle development. Together, our findings indicate that RCOR1 acts in concert with LSD1 as a novel positive regulator of myogenesis and skeletal muscle regeneration.