Pearen Michael A, Eriksson Natalie A, Fitzsimmons Rebecca L, Goode Joel M, Martel Nick, Andrikopoulos Sofianos, Muscat George E O
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.
Mol Endocrinol. 2012 Mar;26(3):372-84. doi: 10.1210/me.2011-1274. Epub 2012 Jan 26.
Nuclear hormone receptors (NR) have been implicated as regulators of lipid and carbohydrate metabolism. The orphan NR4A subgroup has emerged as regulators of metabolic function. Targeted silencing of neuron-derived orphan receptor 1 (Nor-1)/NR4A3 in skeletal muscle cells suggested that this NR was necessary for oxidative metabolism in vitro. To investigate the in vivo role of Nor-1, we have developed a mouse model with preferential expression of activated Nor-1 in skeletal muscle. In skeletal muscle, this resulted in a marked increase in: 1) myoglobin expression, 2) mitochondrial DNA and density, 3) oxidative enzyme staining, and 4) genes/proteins encoding subunits of electron transport chain complexes. This was associated with significantly increased type IIA and IIX myosin heavy chain mRNA and proteins and decreased type IIB myosin heavy chain mRNA and protein. The contractile protein/fiber type remodeling driving the acquisition of the oxidative type II phenotype was associated with 1) the significantly increased expression of myocyte-specific enhancer factor 2C, and phospho-histone deacetylase 5, and 2) predominantly cytoplasmic HDAC5 staining in the Tg-Nor-1 mice. Moreover, the Nor-1 transgenic line displayed significant improvements in glucose tolerance, oxygen consumption, and running endurance (in the absence of increased insulin sensitivity), consistent with increased oxidative capacity of skeletal muscle. We conclude that skeletal muscle fiber type is not only regulated by exercise-sensitive calcineurin-induced signaling cascade but also by NR signaling pathways that operate at the nexus that coordinates muscle performance and metabolic capacity in this major mass tissue.
核激素受体（NR）被认为是脂质和碳水化合物代谢的调节因子。孤儿核受体4A亚组已成为代谢功能的调节因子。在骨骼肌细胞中靶向沉默神经元衍生的孤儿受体1（Nor-1）/NR4A3表明，这种核受体在体外氧化代谢中是必需的。为了研究Nor-1在体内的作用，我们构建了一种在骨骼肌中优先表达活化型Nor-1的小鼠模型。在骨骼肌中，这导致了以下显著增加：1）肌红蛋白表达；2）线粒体DNA和密度；3）氧化酶染色；4）编码电子传递链复合物亚基的基因/蛋白质。这与IIA型和IIX型肌球蛋白重链mRNA和蛋白质显著增加以及IIB型肌球蛋白重链mRNA和蛋白质减少有关。驱动氧化型II型表型获得的收缩蛋白/纤维类型重塑与以下因素有关：1）肌细胞特异性增强因子2C和磷酸化组蛋白脱乙酰酶5的表达显著增加；2）在转基因Nor-1小鼠中，HDAC5主要在细胞质中染色。此外，Nor-1转基因品系在葡萄糖耐量、耗氧量和跑步耐力方面有显著改善（在胰岛素敏感性未增加的情况下），这与骨骼肌氧化能力增加一致。我们得出结论，骨骼肌纤维类型不仅受运动敏感的钙调神经磷酸酶诱导的信号级联调节，还受在协调这一主要组织中肌肉性能和代谢能力的连接点起作用的核受体信号通路调节。
