title: Rev-erb-α modulates skeletal muscle oxidative capacity by regulating mitochondrial biogenesis and autophagy.
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.
authors.affiliation: Institut Pasteur de Lille, Lille, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Woldt
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Sebti
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Christian
authors.initials: C
authors.lastname: Duhem
authors.forename: Steve
authors.initials: S
authors.lastname: Lancel
authors.forename: Jérôme
authors.initials: J
authors.lastname: Eeckhoute
authors.forename: Matthijs K C
authors.initials: MK
authors.lastname: Hesselink
authors.forename: Charlotte
authors.initials: C
authors.lastname: Paquet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Delhaye
authors.forename: Youseung
authors.initials: Y
authors.lastname: Shin
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Kamenecka
authors.forename: Gert
authors.initials: G
authors.lastname: Schaart
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.forename: Rémi
authors.initials: R
authors.lastname: Nevière
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Burris
authors.forename: Patrick
authors.initials: P
authors.lastname: Schrauwen
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Hélène
authors.initials: H
authors.lastname: Duez
mesh_terms: D000818:Animals; D001343:Autophagy; D019069:Cell Respiration; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism / Q000648:ultrastructure; D063269:Mitochondrial Turnover; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000166:cytology* / Q000378:metabolism* / Q000648:ultrastructure; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000172:deficiency / Q000378:metabolism*; D010084:Oxidation-Reduction; D010805:Physical Conditioning, Animal; D015398:Signal Transduction; D013997:Time Factors
chemical_list: C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1