Rev-erb-α controls skeletal muscle calcium homeostasis through myoregulin repression: implications in Duchenne Muscular Dystrophy

Abstract

The sarcoplasmic reticulum (SR) plays an important role in calcium homeostasis. SR calcium mishandling is described in pathological conditions such as myopathies. Here, we investigated whether the nuclear receptor Rev-erb- regulates skeletal muscle SR calcium homeostasis. Our data demonstrate that Rev-erb invalidation in mice impairs SERCA-dependent SR calcium uptake. Rev-erb- acts on calcium homeostasis by repressing the SERCA inhibitor Myoregulin, through direct binding to its promoter. Restoration of Myoregulin counteracts the effects of REV-ERB- overexpression on SR calcium content. Interestingly, myoblasts from Duchenne myopathy patients display downregulated REV-ERB expression, whereas pharmacological Rev-erb activation ameliorates SR calcium homeostasis, and improves muscle structure and function in dystrophic mdx/Utr+/- mice. Our findings demonstrate that Rev-erb- regulates muscle SR calcium homeostasis, pointing to its therapeutic interest for mitigating myopathy.