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

Nat Med. 2013 Aug;19(8):1039-46. doi: 10.1038/nm.3213. Epub 2013 Jul 14.

Abstract

The nuclear receptor Rev-erb-α modulates hepatic lipid and glucose metabolism, adipogenesis and the inflammatory response in macrophages. We show here that Rev-erb-α 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-α deficiency resulted in deactivation of the Lkb1-Ampk-Sirt1-Ppargc-1α signaling pathway. These effects were recapitulated in isolated fibers and in muscle cells after knockdown of the gene encoding Rev-erb-α, Nr1d1. In complementary experiments, Rev-erb-α overexpression in vitro increased the number of mitochondria and improved respiratory capacity, whereas muscle overexpression or pharmacological activation of Rev-erb-α in vivo increased exercise capacity. This study identifies Rev-erb-α as a pharmacological target that improves muscle oxidative function by modulating gene networks controlling mitochondrial number and function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Cell Respiration
  • Mice
  • Mitochondria, Muscle / metabolism
  • Mitochondria, Muscle / ultrastructure
  • Mitochondrial Turnover*
  • Motor Activity
  • Muscle, Skeletal / cytology*
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / ultrastructure
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / deficiency
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Oxidation-Reduction
  • Physical Conditioning, Animal
  • Signal Transduction
  • Time Factors

Substances

  • Nr1d1 protein, mouse
  • Nuclear Receptor Subfamily 1, Group D, Member 1