Skeletal muscle PGC-1a mediates mitochondrial, but not metabolic, changes during calorie restriction

Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation and reactive oxygen species scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1a is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1a activity. To test this model for the first time, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1a (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1a is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy demonstrated that PGC-1a is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1a is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1a nor mitochondrial biogenesis in skeletal muscle are required for the metabolic benefits of CR. Control (FLOX) and PGC-1a skeletal muscle specific knock out (MKO) mice were placed on a control diet [C] or a calorie restriction diet [CR] for 12 weeks. RNA was isolated from TA/EDL muscles for microarray analysis. The following numbers of mice were analyzed from each group: C FLOX: n = 6; C MKO: n = 7; CR FLOX: n = 6; CR MKO: n = 7. Mice were mixed C57/BL6 and 129 background.热量限制（Calorie restriction, CR）是一类可在多种生物中延长寿命与健康寿命的饮食干预手段。CR可改善骨骼肌及其他组织的线粒体能量生成、燃料氧化与活性氧清除能力，上述过程被认为是CR发挥有益作用的关键。过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC-1a）是一类调控线粒体功能的转录辅激活因子，可被CR诱导表达。因此，CR所带来的诸多线粒体与代谢益处，被归因于PGC-1a活性的增强。 为首次验证这一假说，我们对骨骼肌特异性PGC-1a敲除小鼠（MKO）开展CR干预下的代谢与线粒体响应研究。令人意外的是，MKO小鼠在CR干预后仍可正常改善葡萄糖稳态，这表明骨骼肌PGC-1a并非CR产生全身益处所必需。与之相反，基因表达谱分析与电子显微镜观测结果显示，PGC-1a是CR诱导骨骼肌线粒体基因表达上调与线粒体密度增加的必要条件。 本研究结果表明，PGC-1a是骨骼肌中CR介导的线粒体响应的主要调控因子，但意外的是，无论是PGC-1a还是骨骼肌线粒体生物发生，均非CR代谢益处所必需。 对照组（FLOX）与骨骼肌特异性PGC-1a敲除（MKO）小鼠分别被饲喂普通饲料[C]与热量限制饲料[CR]，干预时长为12周。从胫骨前肌（TA）与伸趾长肌（EDL）中提取RNA，用于基因芯片分析。各组分析的小鼠数量如下：普通饲料对照FLOX组（C FLOX）：n=6；普通饲料对照MKO组（C MKO）：n=7；热量限制饲料FLOX组（CR FLOX）：n=6；热量限制饲料MKO组（CR MKO）：n=7。实验小鼠为C57/BL6与129混合遗传背景。