Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required.
Mitochondrial biogenesis and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) deacetylation by physical activity: intact adipocytokine signaling is required.
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DOI：
10.2337/db10-0331
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发表时间：
2011-01
期刊：
影响因子：
7.7
通讯作者：
Rohrbach S
中科院分区：
文献类型：
--
作者：
Li L;Pan R;Li R;Niemann B;Aurich AC;Chen Y;Rohrbach S
转录过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）在线粒体生物合成和能量代谢中起关键作用，并被认为参与运动诱导的线粒体含量增加。PGC-1α活性受翻译后修饰调节，其中包括乙酰化或磷酸化。因此，脱乙酰酶SIRT 1和激酶AMPK增加PGC-1α活性。我们测试了与C57 BL/6 J野生型小鼠相比，慢性跑台运动或单次运动是否会改变脂联素/瘦素介导的AMPK激活失调的肥胖ob/ob小鼠的PGC-1α激活和线粒体生物发生的差异。运动训练（12周）诱导脂联素和降低血浆胰岛素和葡萄糖，表明野生型小鼠胰岛素敏感性改善。它增强了红色腓肠肌线粒体生物合成，如转录调节因子和初级线粒体转录物的mRNA表达增加，mtDNA含量增加和柠檬酸合酶活性增加所示。与此同时，我们在训练过的野生型小鼠中观察到AMPK激活、PGC-1α去乙酰化和SIRT 1诱导。虽然在ob/ob小鼠中没有检测到这些运动诱导的变化，但观察到对线粒体呼吸的类似影响。单次运动导致野生型小鼠的变化相当。这些变化在运动后6小时仍可检测到，但在24小时后消失。用瘦素或脂联素处理C2 C12成肌细胞导致AMPK磷酸化和PGC-1α去乙酰化增加。慢性运动诱导野生型小鼠线粒体生物发生，这可能需要脂肪细胞因子完整的AMPK激活，并涉及SIRT 1依赖性PGC-1α脱乙酰化。经过训练的ob/ob小鼠似乎已经部分适应了通过AMPK/SIRT 1/PGC-1α非依赖性机制减少的线粒体生物合成，而没有mtDNA复制。
Transcriptional peroxisome proliferator–activated receptor-γ coactivator-1α (PGC-1α) plays a key role in mitochondrial biogenesis and energy metabolism and is suggested to be involved in the exercise-induced increase in mitochondrial content. PGC-1α activity is regulated by posttranslational modifications, among them acetylation or phosphorylation. Accordingly, the deacetylase SIRT1 and the kinase AMPK increase PGC-1α activity. We tested whether chronic treadmill exercise or a single exercise session modifies PGC-1α activation and mitochondrial biogenesis differentially in obese ob/ob mice with dysregulated adiponectin/leptin-mediated AMPK activation compared with C57BL/6J wild-type mice. Exercise training (12 weeks) induced adiponectin and lowered plasma insulin and glucose, suggesting improved insulin sensitivity in wild-type mice. It enhanced mitochondrial biogenesis in red gastrocnemius muscle, as indicated by increased mRNA expression of transcriptional regulators and primary mitochondrial transcripts, increased mtDNA content, and citrate synthase activity. Parallel to this, we observed AMPK activation, PGC-1α deacetylation, and SIRT1 induction in trained wild-type mice. Although none of these exercise-induced changes were detected in ob/ob mice, comparable effects on mitochondrial respiration were observed. A single exercise session resulted in comparable changes in wild-type mice. These changes remained detectable 6 h after the exercise session but had disappeared after 24 h. Treatment of C2C12 myoblasts with leptin or adiponectin resulted in increased AMPK phosphorylation and PGC-1α deacetylation. Chronic exercise induces mitochondrial biogenesis in wild-type mice, which may require intact AMPK activation by adipocytokines and involve SIRT1-dependent PGC-1α deacetylation. Trained ob/ob mice appear to have partially adapted to reduced mitochondrial biogenesis by AMPK/SIRT1/PGC-1α–independent mechanisms without mtDNA replication.