Cell Metabolism
Volume 11, Issue 3, 3 March 2010, Pages 213-219
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Short Article
Interdependence of AMPK and SIRT1 for Metabolic Adaptation to Fasting and Exercise in Skeletal Muscle

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Summary

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-1α 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-1α 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.

Highlights

► AMPK activation increases NAD+ levels and SIRT1 activity during energy stress ► Metabolic flexibiilty to choose between energy sources is dependent on AMPK ► SIRT1 activation is impaired in AMPKγ3 KO mice in response to fasting and exercise ► Resveratrol requires AMPK to activate SIRT1

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