AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α
AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α
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DOI：
10.1073/pnas.0705070104
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发表时间：
2007-07-17
影响因子：
11.1
通讯作者：
Spiegelman, Bruce M.
中科院分区：
文献类型：
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作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
骨骼肌中AMP激活激酶（AMPK）的激活通过增加这些途径中的基因表达来增加葡萄糖摄取、脂肪酸氧化和线粒体生物合成。然而，AMPK直接靶向的转录组分仍然难以捉摸。过氧化物酶体增殖物激活受体γ辅激活因子1a（PGC-1 α）已成为线粒体生物发生的主要调节因子;此外，已表明PGC-1 α基因表达由运动和骨骼肌中AMPK的化学激活诱导。使用原代肌细胞和PGC-1a缺陷小鼠，我们发现AMPK对葡萄糖转运蛋白4、线粒体基因和PGC-1 α本身基因表达的影响几乎完全依赖于PGC-1a蛋白的功能。此外，AMPK在体外和细胞中直接磷酸化PGC-1a。PGC-1 α蛋白在苏氨酸-177和丝氨酸-538处的这些直接磷酸化是PGC-1 α启动子的PGC-1 α依赖性诱导所需的。这些数据表明，PGC-1a的AMPK磷酸化启动了AMPK在骨骼肌中的许多重要基因调节功能。
Activation of AMP-activated kinase (AMPK) in skeletal muscle increases glucose uptake, fatty acid oxidation, and mitochondrial biogenesis by increasing gene expression in these pathways. However, the transcriptional components that are directly targeted by AMPK are still elusive. The peroxisome-proliferator-activated receptor gamma coactivator 1a (PGC-1 alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1 alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1a, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1 alpha itself are almost entirely dependent on the function of PGC-1a protein. Furthermore, AMPK phosphorylates PGC-1a directly both in vitro and in cells. These direct phosphorylations of the PGC-1a protein at threonine-177 and serine-538 are required for the PGC-la-dependent induction of the PGC-1 alpha promoter. These data indicate that AMPK phosphorylation of PGC-1a initiates many of the important gene regulatory functions of AMPK in skeletal muscle.