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