期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 29, 页码 12017-12022出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0705070104
关键词
mitochondria; respiration
资金
- NIDDK NIH HHS [R56 DK054477, DK54477, P30 DK040561-12, P30 DK040561, R01 DK054477] Funding Source: Medline
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.
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