Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle.
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-1alpha 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-1alpha 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.
Cantó
Carles
C
Ecole Polytechnique Fédérale de Lausanne, Switzerland.
Jiang
Lake Q
LQ
Deshmukh
Atul S
AS
Mataki
Chikage
C
Coste
Agnes
A
Lagouge
Marie
M
Zierath
Juleen R
JR
Auwerx
Johan
J
D055372:AMP-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050259:Genes, Mitochondrial / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D008055:Lipids / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010805:Physical Conditioning, Animal / Q000502:physiology*; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D015854:Up-Regulation / Q000235:genetics
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D008055:Lipids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C548179:Prkaa1 protein, mouse; C526221:Prkag3 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005947:Glucose