Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization[S]
| Autor: | Cynthia Hong, Karen Reue, Lily C. Chao, Kevin Wroblewski, Simon Schenk, Ronald M. Evans, Leonel Martinez, Vihang A. Narkar, Laurent Vergnes, Melissa J. Spencer, Andrea L. Hevener, Robert Stevens, Gretchen A. Meyer, James R. Bain, Brian G. Drew, Peter Tontonoz, Christopher B. Newgard, Olga Ilkayeva, Rima Boyadjian |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Genetically modified mouse
Mitochondrial DNA Bioenergetics Mice Transgenic Oxidative phosphorylation QD415-436 Mitochondrion Biology DNA Mitochondrial Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Nuclear Receptor Subfamily 4 Group A Member 1 medicine Animals nuclear receptor Muscle Skeletal Promoter Regions Genetic Creatine Kinase Beta oxidation Research Articles 030304 developmental biology 0303 health sciences Skeletal muscle Cell Biology Metabolism Nr4a Mitochondria Muscle Mice Inbred C57BL mitochondria medicine.anatomical_structure Oxidation-Reduction 030217 neurology & neurosurgery |
| Zdroj: | Journal of Lipid Research, Vol 53, Iss 12, Pp 2610-2619 (2012) Journal of Lipid Research |
| ISSN: | 0022-2275 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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