Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center, Houston, Texas, USA.
Center for Precision Medicine, School of Biomedical Informatics, The University of Texas Health Science Center, Houston, Texas, USA.
FASEB J. 2023 Feb;37(2):e22727. doi: 10.1096/fj.202201518R.
Transcriptional determinants in the skeletal muscle that govern exercise capacity, while poorly defined, could provide molecular insights into how exercise improves fitness. Here, we have elucidated the role of nuclear receptors, estrogen-related receptor alpha and gamma (ERRα/γ) in regulating myofibrillar composition, contractility, and exercise capacity in skeletal muscle. We used muscle-specific single or double (DKO) ERRα/γ knockout mice to investigate the effect of ERRα/γ deletion on muscle and exercise parameters. Individual knockout of ERRα/γ did not have a significant impact on the skeletal muscle. On the other hand, DKO mice exhibit pale muscles compared to wild-type (WT) littermates. RNA-seq analysis revealed a predominant decrease in expression of genes linked to mitochondrial and oxidative metabolism in DKO versus WT muscles. DKO muscles exhibit marked repression of oxidative enzymatic capacity, as well as mitochondrial number and size compared to WT muscles. Mitochondrial function is also impaired in single myofibers isolated from DKO versus WT muscles. In addition, mutant muscles exhibit reduced angiogenic gene expression and decreased capillarity. Consequently, DKO mice have a significantly reduced exercise capacity, further reflected in poor fatigue resistance of DKO mice in in vivo contraction assays. These results show that ERRα and ERRγ together are a critical link between muscle aerobic capacity and exercise tolerance. The ERRα/γ mutant mice could be valuable for understanding the long-term impact of impaired mitochondria and vascular supply on the pathogenesis of muscle-linked disorders.
虽然控制运动能力的骨骼肌转录决定因素尚未完全明确，但它们可能为了解运动如何改善健康状况提供分子层面的认识。在这里，我们阐明了核受体、雌激素相关受体α和γ（ERRα/γ）在调节骨骼肌肌原纤维组成、收缩性和运动能力中的作用。我们使用肌肉特异性单敲除或双敲除（DKO）ERRα/γ敲除小鼠来研究 ERRα/γ缺失对肌肉和运动参数的影响。ERRα/γ 的单独敲除对骨骼肌没有显著影响。另一方面，与野生型（WT）同窝仔相比，DKO 小鼠的肌肉呈现苍白。RNA-seq 分析显示，与 WT 肌肉相比，DKO 肌肉中与线粒体和氧化代谢相关的基因表达显著降低。与 WT 肌肉相比，DKO 肌肉中的氧化酶活性、线粒体数量和大小明显受到抑制。来自 DKO 与 WT 肌肉的单个肌纤维的线粒体功能也受损。此外，突变肌肉表现出血管生成基因表达减少和毛细血管密度降低。因此，与 WT 小鼠相比，DKO 小鼠的运动能力显著降低，这进一步反映在 DKO 小鼠在体内收缩试验中的疲劳抵抗能力较差。这些结果表明，ERRα 和 ERRγ 共同构成了肌肉有氧能力和运动耐力之间的关键联系。ERRα/γ 突变小鼠对于理解受损线粒体和血管供应对与肌肉相关疾病的发病机制的长期影响可能非常有价值。
