AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.
AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha.
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DOI：
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发表时间：
2007
影响因子：
11.1
通讯作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
中科院分区：
文献类型：
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作者：
S. Jäger;C. Handschin;J. St-Pierre;B. Spiegelman
骨骼肌中AMP激活的激酶(AMPK)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的生物合成。然而，AMPK直接靶向的转录成分仍然难以捉摸。过氧化物酶体增殖物激活受体γ共激活因子1α(PGC-1α)是线粒体生物发生的主要调节因子，运动和化学激活AMPK均可诱导PGC-1α基因的表达。利用原代肌肉细胞和PGC-1α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-1α基因表达的影响几乎完全依赖于PGC-1α蛋白的功能。此外，AMPK在体外和细胞内都直接磷酸化PGC-1α。PGC-1α蛋白在苏氨酸-177和丝氨酸-538处的这些直接磷酸化是依赖PGC-1α诱导PGC-1α启动子所必需的。这些数据表明，PGC-1α的AMPK磷酸化启动了骨骼肌中AMPK的许多重要的基因调控功能。
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 1alpha (PGC-1alpha) has emerged as a master regulator of mitochondrial biogenesis; furthermore, it has been shown that PGC-1alpha gene expression is induced by exercise and by chemical activation of AMPK in skeletal muscle. Using primary muscle cells and mice deficient in PGC-1alpha, we found that the effects of AMPK on gene expression of glucose transporter 4, mitochondrial genes, and PGC-1alpha itself are almost entirely dependent on the function of PGC-1alpha protein. Furthermore, AMPK phosphorylates PGC-1alpha directly both in vitro and in cells. These direct phosphorylations of the PGC-1alpha protein at threonine-177 and serine-538 are required for the PGC-1alpha-dependent induction of the PGC-1alpha promoter. These data indicate that AMPK phosphorylation of PGC-1alpha initiates many of the important gene regulatory functions of AMPK in skeletal muscle.