Biozentrum, University of Basel, Basel, Switzerland.
Mol Cell Biol. 2012 Dec;32(24):4913-24. doi: 10.1128/MCB.00877-12. Epub 2012 Oct 1.
Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.
骨骼肌具有很高的可塑性，因此可以通过多种表观遗传机制来改变其表型，从而快速适应不同的生理和病理刺激。核受体辅阻遏物 1（NCoR1）具有介导基因抑制的能力；然而，其在调节骨骼肌中生物学程序的作用仍知之甚少。因此，我们研究了 NCoR1 在该组织中的功能的机制和功能方面。NCoR1 肌肉特异性敲除小鼠表现出 7.2%更高的峰值耗氧量（VO(2peak)），最大等长力降低 11%，最大刺激时体外疲劳抵抗力增加。有趣的是，全基因组表达分析显示，NCoR1 缺失和过氧化物酶体增殖物激活受体γ（PPARγ）共激活因子 1α（PGC-1α）过表达对肌肉氧化代谢的影响有很高的重叠。重要的是，PPARβ/δ 和雌激素相关受体α（ERRα）被鉴定为 NCoR1 和 PGC-1α 的共同靶标，它们对这些核受体转录活性的影响相反。事实上，NCoR1 对氧化磷酸化基因表达的抑制作用特别拮抗 PGC-1α 介导的 ERRα 共激活作用。因此，我们描绘了由辅阻遏物和共激活蛋白组成的转录网络决定骨骼肌代谢特性的分子机制，这代表了代谢疾病的潜在治疗靶点。
