title: Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization.
abstract: Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. Identifying novel regulators of mitochondrial bioenergetics will broaden our understanding of regulatory checkpoints that coordinate complex metabolic pathways. We previously showed that Nur77, an orphan nuclear receptor of the NR4A family, regulates the expression of genes linked to glucose utilization. Here we demonstrate that expression of Nur77 in skeletal muscle also enhances mitochondrial function. We generated MCK-Nur77 transgenic mice that express wild-type Nur77 specifically in skeletal muscle. Nur77-overexpressing muscle had increased abundance of oxidative muscle fibers and mitochondrial DNA content. Transgenic muscle also exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Metabolomic analysis confirmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profile of fasting. Nur77 expression also improved the intrinsic respiratory capacity of isolated mitochondria, likely due to the increased abundance of complex I of the electron transport chain. These changes in mitochondrial metabolism translated to improved muscle contractile function ex vivo and improved cold tolerance in vivo. Our studies outline a novel role for Nur77 in the regulation of oxidative metabolism and mitochondrial activity in skeletal muscle.
authors.affiliation: Howard Hughes Medical Institute, Center for Duchenne Muscular Dystrophy at University of California Los Angeles, Los Angeles, CA, USA. lchao@chla.usc.edu
authors.forename: Lily C
authors.initials: LC
authors.lastname: Chao
authors.forename: Kevin
authors.initials: K
authors.lastname: Wroblewski
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.forename: Robert D
authors.initials: RD
authors.lastname: Stevens
authors.forename: James
authors.initials: J
authors.lastname: Bain
authors.forename: Gretchen A
authors.initials: GA
authors.lastname: Meyer
authors.forename: Simon
authors.initials: S
authors.lastname: Schenk
authors.forename: Leonel
authors.initials: L
authors.lastname: Martinez
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.forename: Vihang A
authors.initials: VA
authors.lastname: Narkar
authors.forename: Brian G
authors.initials: BG
authors.lastname: Drew
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Rima
authors.initials: R
authors.lastname: Boyadjian
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Hevener
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Newgard
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D000818:Animals; D003402:Creatine Kinase / Q000235:genetics / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1 / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D003402:Creatine Kinase