Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction
Skeletal muscle transcriptional coactivator PGC-1α mediates mitochondrial, but not metabolic, changes during calorie restriction
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DOI：
10.1073/pnas.1115813109
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发表时间：
2012-02-21
影响因子：
11.1
通讯作者：
Haigis, Marcia C.
中科院分区：
文献类型：
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作者：
Finley, Lydia W. S.;Lee, Jaewon;Haigis, Marcia C.
热量限制（CR）是一种饮食干预，可以延长各种生物体的寿命和健康寿命。CR改善骨骼肌和其他组织中的线粒体能量产生、燃料氧化和活性氧（ROS）清除，这些过程被认为对CR的益处至关重要。PGC-1 α是一种转录辅激活因子，调节线粒体功能，并由CR诱导。因此，CR的许多线粒体和代谢益处归因于增加的PGC-1 α活性。为了测试该模型，我们检查了缺乏骨骼肌PGC-1 α（MKO）的小鼠对CR的代谢和线粒体反应。令人惊讶的是，MKO小鼠表现出对CR的葡萄糖稳态的正常改善，表明骨骼肌PGC-1 α对CR的全身益处不利。相比之下，基因表达谱和电子显微镜（EM）表明，PGC-1 α是所需的完全CR诱导的线粒体基因表达和骨骼肌线粒体密度的增加。这些结果表明，PGC-1 α是骨骼肌中线粒体对CR反应的主要调节因子，但令人惊讶地表明，CR的全身代谢益处既不需要骨骼肌中的PGC-1 α也不需要线粒体生物合成。
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 (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1 alpha 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-1 alpha activity. To test this model, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1 alpha (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1 alpha is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy (EM) demonstrated that PGC-1 alpha is required for the full CR-induced increases in mitochondrial gene expression and mitochondrial density in skeletal muscle. These results demonstrate that PGC-1 alpha is a major regulator of the mitochondrial response to CR in skeletal muscle, but surprisingly show that neither PGC-1 alpha nor mitochondrial biogenesis in skeletal muscle are required for the whole-body metabolic benefits of CR.