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

• Published in: Nature medicine Vol. 19; no. 8; pp. 1039 - 1046
• Main Authors: Woldt, Estelle, Sebti, Yasmine, Solt, Laura A, Duhem, Christian, Lancel, Steve, Eeckhoute, Jérôme, Hesselink, Matthijs K C, Paquet, Charlotte, Delhaye, Stéphane, Shin, Youseung, Kamenecka, Theodore M, Schaart, Gert, Lefebvre, Philippe, Nevière, Rémi, Burris, Thomas P, Schrauwen, Patrick, Staels, Bart, Duez, Hélène
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-08-2013; Nature Publishing Group
• Subjects: 631/443/319; Animals; Autophagy; Autophagy (Cytology); Biomedicine; Cancer Research; Cell receptors; Cell Respiration; Genetic aspects; Infectious Diseases; Metabolic Diseases; Mice; Mitochondria, Muscle - metabolism; Mitochondria, Muscle - ultrastructure; Mitochondrial Turnover; Molecular Medicine; Motor Activity; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscle, Skeletal - ultrastructure; Muscles; Neurosciences; Nuclear Receptor Subfamily 1, Group D, Member 1 - deficiency; Nuclear Receptor Subfamily 1, Group D, Member 1 - metabolism; Oxidation-Reduction; Physical Conditioning, Animal; Physiological aspects; Signal Transduction; Time Factors; France; United States; Netherlands
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3213

Bart Staels and his colleagues show that the transcription factor Rev-erb-α is highly expressed in oxidative muscle and, via loss- and gain-of-function experiments, including pharmacological activation, that it plays a key partin regulating the oxidative capacity of the muscle and exercise endurance.
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.