title: AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1.
abstract: In skeletal muscle, protein levels are determined by relative rates of protein synthesis and breakdown. The balance between synthesis and degradation of intracellular components determines the overall muscle fiber size. AMP-activated protein kinase (AMPK), a sensor of cellular energy status, was recently shown to increase myofibrillar protein degradation through the expression of MAFbx and MuRF1. In the present study, the effect of AMPK activation by AICAR on autophagy was investigated in muscle cells. Our results show that FoxO3a transcription factor activation by AMPK induces the expression of the autophagy-related proteins LC3B-II, Gabarapl1, and Beclin1 in primary mouse skeletal muscle myotubes and in the Tibialis anterior (TA) muscle. Time course studies reveal that AMPK activation by AICAR leads to a transient nuclear relocalization of FoxO3a followed by an increase of its cytosolic level. Moreover, AMPK activation leads to the inhibition of mTORC1 and its subsequent dissociation of Ulk1, Atg13, and FIP200 complex. Interestingly, we identify Ulk1 as a new interacting partner of AMPK in muscle cells and we show that Ulk1 is associated with AMPK under normal conditions and dissociates from AMPK during autophagy process. Moreover, we find that AMPK phosphorylates FoxO3a and Ulk1. In conclusion, our data show that AMPK activation stimulates autophagy in skeletal muscle cells through its effects on the transcriptional function of FoxO3a and takes part in the initiation of autophagosome formation by interacting with Ulk1. Here, we present new evidences that AMPK plays a crucial role in the fine tuning of protein expression programs that control skeletal muscle mass.
authors: INRA, UMR866 Dynamique Musculaire et Métabolisme, 2 Place Viala, F-34060 Montpellier, France. anthony.mj.sanchez@hotmail.fr
authors: Anthony M J
authors: AM
authors: Sanchez
authors: Alfredo
authors: A
authors: Csibi
authors: Audrey
authors: A
authors: Raibon
authors: Karen
authors: K
authors: Cornille
authors: Stéphanie
authors: S
authors: Gay
authors: Henri
authors: H
authors: Bernardi
authors: Robin
authors: R
authors: Candau
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism / Q000502:physiology*; D000595:Amino Acid Sequence; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives; D000818:Animals; D001343:Autophagy; D000071189:Autophagy-Related Protein-1 Homolog; D002460:Cell Line; D017124:Conserved Sequence; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015870:Gene Expression; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology*; D009133:Muscular Atrophy; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism*; D021381:Protein Transport; D011506:Proteins / Q000378:metabolism; D012265:Ribonucleotides; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism
chemical_list: D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; D046912:Multiprotein Complexes; D009124:Muscle Proteins; D011506:Proteins; D012265:Ribonucleotides; D000070584:Tripartite Motif Proteins; D000620:Aminoimidazole Carboxamide; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000071189:Autophagy-Related Protein-1 Homolog; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C112444:Ulk1 protein, mouse; D000263:Adenylate Kinase; C031143:AICA ribonucleotide