Inhibition of Rev-erbα ameliorates muscular dystrophy

Duchene muscular dystrophy leads to progressive muscle structural and functional decline due to chronic degenerative-regenerative cycles. Enhancing the regenerative capacity of dystrophic muscle provides potential therapeutic options. We previously demonstrated that the circadian clock repressor Rev-erb alpha inhibited myogenesis and Rev-erb alpha ablation enhanced muscle regeneration. Here we show that Rev-erb alpha deficiency in the dystrophin-deficient mdx mice promotes regenerative myogenic response to ameliorate muscle damage. Loss of Rev-erb alpha in mdx mice improved dystrophic pathology and muscle wasting. Rev-erb alpha-deficient dystrophic muscle exhibit augmented myogenic response, enhanced neo-myofiber formation and attenuated inflammatory response. In mdx myoblasts devoid of Rev-erb alpha, myogenic differentiation was augmented together with up-regulation of Wnt signaling and proliferative pathways, suggesting that loss of Rev-erb alpha inhibition of these processes contributed to the improvement in regenerative myogenesis. Collectively, our findings revealed that the loss of Rev-erb alpha function protects dystrophic muscle from injury by promoting myogenic repair, and inhibition of its activity may have therapeutic utilities for muscular dystrophy.

Automated summary

The deficiency of Rev-erb alpha in mdx mice promotes regenerative myogenic response, ameliorates muscle damage, and enhances the regenerative capacity of dystrophic muscle.