Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression
Exercise-induced mitochondrial biogenesis begins before the increase in muscle PGC-1α expression
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DOI：
10.1074/jbc.m606116200
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发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Holloszy, John O.
中科院分区：
文献类型：
--
作者：
Wright, David C.;Han, Dong-Ho;Holloszy, John O.
运动可导致骨骼肌中转录辅活化子、过氧化物酶体增殖物激活受体γ辅活化子-1α(PGC-1α)的表达迅速增加，并促进线粒体的生物发生。PGC-1a调节和协调线粒体的生物发生，PGC-1α在肌肉细胞中的过表达导致线粒体含量的增加。在此背景下，有人提出，PGC-1α蛋白表达的增加介导了运动诱导的线粒体生物发生的增加。然而，我们发现半衰期短的线粒体蛋白的增加速度与PGC-1α蛋白一样快，甚至更快。这一发现使我们假设，PGC-1α的激活，而不是表达的增加，介导了运动诱导的线粒体增加的初始阶段。在本研究中，我们发现静息骨骼肌中的PGC-1α大部分存在于胞浆中。运动导致p38MAPK激活和PGC-1α向核内移动。为了支持我们的假设，在PGC-1α蛋白增加之前，转录因子核呼吸因子1(NRF-1)与细胞色素c启动子的结合以及NRF-2与细胞色素氧化酶亚单位4启动子的结合随着运动的反应而增加。此外，运动诱导的细胞色素c、β-氨基酮丙酸合成酶和柠檬酸合成酶的mRNAs的增加也发生在PGC-1蛋白的增加之前。因此，PGC-1α的激活可能介导了运动诱导的肌肉线粒体适应性增加的初始阶段，而随后PGC-1α蛋白的增加维持并促进了线粒体生物发生的增加。
Exercise results in rapid increases in expression of the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) and in mitochondrial biogenesis in skeletal muscle. PGC-1a regulates and coordinates mitochondrial biogenesis, and overexpression of PGC-1 alpha in muscle cells results in increases in mitochondrial content. In this context, it has been proposed that the increase in PGC-1 alpha protein expression mediates the exercise-induced increase in mitochondrial biogenesis. However, we found that mitochondrial proteins with a short half-life increase as rapidly as, or more rapidly than, PGC-1 alpha protein. This finding led us to hypothesize that activation, rather than increased expression, of PGC-1 alpha mediates the initial phase of the exercise-induced increase in mitochondria. In this study, we found that most of the PGC-1 alpha in resting skeletal muscle is in the cytosol. Exercise resulted in activation of p38 MAPK and movement of PGC-1 alpha into the nucleus. In support of our hypothesis, binding of the transcription factor nuclear respiratory factor 1 (NRF-1) to the cytochrome c promoter and NRF-2 to the cytochrome oxidase subunit 4 promoter increased in response to exercise prior to an increase in PGC-1 alpha protein. Furthermore, exercise-induced increases in the mRNAs of cytochrome c, delta-aminolevulinate synthase, and citrate synthase also occurred before an increase in PGC-1 protein. Thus, it appears that activation of PGC-1 alpha may mediate the initial phase of the exercise-induced adaptive increase in muscle mitochondria, whereas the subsequent increase in PGC-1 alpha protein sustains and enhances the increase in mitochondrial biogenesis.