Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Chao, LC; Wroblewski, K; Ilkayeva, OR; Stevens, RD; Bain, J; Meyer, GA; Schenk, S; Martinez, L; Vergnes, L; Narkar, VA; Drew, BG; Hong, C; Boyadjian, R; Hevener, AL; Evans, RM; Reue, K; Spencer, MJ; Newgard, CB; Tontonoz, P

Published Date

  • December 2012

Published In

Volume / Issue

  • 53 / 12

Start / End Page

  • 2610 - 2619

PubMed ID

  • 23028113

Pubmed Central ID

  • 23028113

Electronic International Standard Serial Number (EISSN)

  • 1539-7262

Digital Object Identifier (DOI)

  • 10.1194/jlr.M029355

Language

  • eng

Conference Location

  • United States