Division of Cardiovascular Disease, Department of Medicine, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, United States.
Am J Physiol Regul Integr Comp Physiol. 2023 Apr 1;324(4):R470-R479. doi: 10.1152/ajpregu.00241.2022. Epub 2023 Jan 30.
The peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1) family of transcriptional coactivators are regulators of mitochondrial oxidative capacity and content in skeletal muscle. Many of these conclusions are based primarily on gain-of-function studies using muscle-specific overexpression of PGC1s. We have previously reported that genetic deletion of both PGC-1α and PGC-1β in adult skeletal muscle resulted in a significant reduction in oxidative capacity with no effect on mitochondrial content. However, the contribution of PGC-1-related coactivator (PRC), the third PGC-1 family member, in regulating skeletal muscle mitochondria is unknown. Therefore, we generated an inducible skeletal muscle-specific PRC knockout mouse (iMS-PRC-KO) to assess the contribution of PRC in skeletal muscle mitochondrial function. We measured mRNA expression of electron transport chain (ETC) subunits as well as markers of mitochondrial content in the iMS-PRC-KO animals and observed an increase in ETC gene expression and mitochondrial content. Furthermore, the increase in ETC gene expression and mitochondrial content was associated with increased expression of PGC-1α and PGC-1β. We therefore generated an adult-inducible PGC-1 knockout mouse in which all PGC-1 family members are deleted (iMS-PGC-1TKO). The iMS-PGC-1TKO animals exhibited a reduction in ETC mRNA expression and mitochondrial content. These data suggest that in the absence of PRC alone, compensation occurs by increasing PGC-1α and PGC-1β to maintain mitochondrial content. Moreover, the removal of all three PGC-1s in skeletal muscle results in a reduction in both ETC mRNA expression and mitochondrial content. Taken together, these results suggest that PRC plays a role in maintaining baseline mitochondrial content in skeletal muscle.
过氧化物酶体增殖物激活受体 γ 共激活因子 1（PGC-1）家族转录共激活因子是骨骼肌中线粒体氧化能力和含量的调节剂。这些结论主要基于使用肌肉特异性过表达 PGC1s 的功能获得研究。我们之前曾报道过，成年骨骼肌中 PGC-1α 和 PGC-1β 的基因缺失导致氧化能力显著降低，而对线粒体含量没有影响。然而，PGC-1 相关共激活因子（PRC），即第三个 PGC-1 家族成员，在调节骨骼肌线粒体中的作用尚不清楚。因此，我们生成了一种可诱导的骨骼肌特异性 PRC 敲除小鼠（iMS-PRC-KO），以评估 PRC 在骨骼肌线粒体功能中的作用。我们测量了 iMS-PRC-KO 动物中线粒体电子传递链（ETC）亚基的 mRNA 表达以及线粒体含量的标志物，观察到 ETC 基因表达和线粒体含量增加。此外，ETC 基因表达和线粒体含量的增加与 PGC-1α 和 PGC-1β 的表达增加有关。因此，我们生成了一种成年可诱导 PGC-1 敲除小鼠，其中所有 PGC-1 家族成员均被删除（iMS-PGC-1TKO）。iMS-PGC-1TKO 动物的 ETC mRNA 表达和线粒体含量降低。这些数据表明，在单独缺乏 PRC 的情况下，通过增加 PGC-1α 和 PGC-1β 来代偿以维持线粒体含量。此外，骨骼肌中所有三种 PGC-1 的缺失都会导致 ETC mRNA 表达和线粒体含量降低。总之，这些结果表明 PRC 在维持骨骼肌中线粒体的基础含量方面发挥作用。
