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.
Highlights
Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes
We previously showed that Nur77 regulates the expression of a battery of glucose utilization genes in fast-twitch muscle fibers [9]
We postulate that Nur77-mediated induction of gene expression in these lines may be limited by the fact that Nur77, as well as its target genes involved in glucose utilization, are already abundantly expressed in skeletal muscle, such that additional transcriptional input may have limited impact on augmenting expression
Summary
Mitochondrial dysfunction has been implicated in the pathogenesis of type 2 diabetes. We demonstrate that expression of Nur in skeletal muscle enhances mitochondrial function. Transgenic muscle exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Nur expression 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 Nur in the regulation of oxidative metabolism and mitochondrial activity in skeletal muscle.—Chao, L. Skeletal muscle Nur expression enhances oxidative metabolism and substrate utilization. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other granting agencies. ˔Author’s Choice—Final version full access
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