Skeletal muscle Nur 77 expression enhances oxidative metabolism and substrate utilization

The mitochondrion is an indispensable component for cellular respiration. To meet ongoing energy demands, cells up-regulate oxidative metabolism to boost ATP production. In skeletal muscle, a number of transcriptional factors have been shown to affect mitochondrial function and biogenesis. Peroxisome proliferator activated receptor  coactivator 1  (Pgc1 ), for instance, coactivates a number of nuclear receptors and transcription factors (estrogen-related receptor , nuclear respiratory factor [Nrf]1, and Nrf2) to promote mitochondrial biogenesis ( 1–4 ). Overexpression of peroxisome proliferator activated receptor delta in skeletal muscle also increases the abundance of slow-twitch muscle fi ber and mitochondrial biogenesis ( 5 ). Uncovering novel biologic regulators that control mitochondrial function is fundamental to unraveling the complex metabolic pathways that control substrate utilization and energy metabolism. 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 specifi cally in skeletal muscle. Nur77-overexpressing muscle had increased abundance of oxidative muscle fi bers and mitochondrial DNA content. Transgenic muscle also exhibited enhanced oxidative metabolism, suggestive of increased mitochondrial activity. Metabolomic analysis confi rmed that Nur77 transgenic muscle favored fatty acid oxidation over glucose oxidation, mimicking the metabolic profi le 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. —Chao, L. C., K. Wroblewski, O. R. Ilkayeva, R. D. Stevens, J. Bain, G. A. Meyer, S. Schenk, L. Martinez, L. Vergnes, V. A. Narkar, B. G. Drew, C. Hong, R. Boyadjian, A. L. Hevener, R. M. Evans, K. Reue, M. J. Spencer, C. B. Newgard, and P. Tontonoz. Skeletal muscle Nur77 expression enhances oxidative metabolism and substrate utilization. J. Lipid Res . 2012. 53: 2610–2619.