The Nuclear Receptor and Clock Repressor Rev-erb\u03b1 Suppresses Myogenesis

Abstract

Rev-erbα is a ligand-dependent nuclear receptor and a key repressor of the molecular clock transcription network. Accumulating evidence indicate that the circadian clock machinery governs diverse biological processes in skeletal muscle, including muscle growth, repair and mass maintenance. The physiological function of Rev-erbα in myogenic regulation remains largely unknown. Here we show that Rev-erbα exerts cell-autonomous inhibitory effects on proliferation and differentiation of myogenic precursor cells, and these actions concertedly inhibit muscle regeneration in vivo. Mechanistic studies reveal Rev-erbα direct transcriptional control of two major myogenic mechanisms, proliferative pathway and the Wnt signaling cascade. Consistent with this finding, primary myoblasts lacking Rev-erbα display significantly enhanced proliferative growth and myogenic progression. Furthermore, pharmacological activation of Rev-erbα activity attenuates, whereas its inhibition by an antagonist promotes these processes. Notably, upon muscle injury, the loss-of-function of Rev-erbα in vivo augmented satellite cell proliferative expansion and regenerative progression during regeneration. Collectively, our study identifies Rev-erbα as a novel inhibitory regulator of myogenic progenitor cell properties that suppresses postnatal myogenesis. Pharmacological interventions to dampen Rev-erbα activity may have potential utilities to enhance regenerative capacity in muscle diseases.