Journal
CELL METABOLISM
Volume 11, Issue 3, Pages 213-219Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2010.02.006
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Funding
- Ecole Polytechnique Federale de Lausanne
- Swiss National Science Foundation
- National Institutes of Health (NIH) [DK59820]
- Swedish Research Council
- Swedish Foundation for Strategic Research
- EU FP6 [LSHM-CT-2004-512013]
- European Research Council Ideas program [ERC-2008-AdG23118, ERC-2008-AdG23285]
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During fasting and after exercise, skeletal muscle efficiently switches from carbohydrate to lipid as the main energy source to preserve glycogen stores and blood glucose levels for glucose-dependent tissues. Skeletal muscle cells sense this limitation in glucose availability and transform this information into transcriptional and metabolic adaptations. Here we demonstrate that AMPK acts as the prime initial sensor that translates this information into SIRT1-dependent deacetylation of the transcriptional regulators PGC-1 alpha and FOXO1, culminating in the transcriptional modulation of mitochondrial and lipid utilization genes. Deficient AMPK activity compromises SIRT1-dependent responses to exercise and fasting, resulting in impaired PGC-1 alpha deacetylation and blunted induction of mitochondrial gene expression. Thus, we conclude that AMPK acts as the primordial trigger for fasting- and exercise-induced adaptations in skeletal muscle and that activation of SIRT1 and its downstream signaling pathways are improperly triggered in AMPK-deficient states.
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