Rev-erb-α regulates atrophy-related genes to control skeletal muscle mass

The nuclear receptor Rev-erb-alpha modulates hepatic lipid and glucose metabolism, adipogenesis and thermogenesis. We have previously demonstrated that Rev-erb-alpha is also an important regulator of skeletal muscle mitochondrial biogenesis and function, and autophagy. As such, Rev-erb-alpha overexpression in skeletal muscle or its pharmacological activation improved mitochondrial respiration and enhanced exercise capacity. Here, in gain-and loss-of function studies, we show that Rev-erb-alpha also controls muscle mass. Rev-erb-alpha-deficiency in skeletal muscle leads to increased expression of the atrophy-related genes (atrogenes), associated with reduced muscle mass and decreased fiber size. By contrast, in vivo and in vitro Rev-erb-alpha over-expression results in reduced atrogenes expression and increased fiber size. Finally, Rev-erb-alpha pharmacological activation blocks dexamethasone-induced upregulation of atrogenes and muscle atrophy. This study identifies Rev-erb-alpha as a promising pharmacological target to preserve muscle mass.