Rev-erb-alpha modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy

The nuclear receptor Rev-erb-alpha modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-alpha is highly expressed in oxidative skeletal muscle and that its deficiency in muscle leads to reduced mitochondrial content and oxidative function, as well as upregulation of autophagy. These cellular effects resulted in both impaired mitochondrial biogenesis and increased clearance of this organelle, leading to compromised exercise capacity. On a molecular level, Rev-erb-alpha deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1 alpha signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-alpha, Nr1d1. In complementary experiments, Rev-erb-alpha overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-alpha in vivo increased exercise capacity. This study identifies Rev-erb-alpha as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.