title: Coordinated maintenance of muscle cell size control by AMP-activated protein kinase.
abstract: Skeletal muscle mass is regulated by signaling pathways that govern protein synthesis and cell proliferation, and the mammalian target of rapamycin (mTOR) plays a key role in these processes. Recent studies suggested the crucial role of AMP-activated protein kinase (AMPK) in the inhibition of protein synthesis and cell growth. Here, we address the role of AMPK in the regulation of muscle cell size in vitro and in vivo. The size of AMPK-deficient myotubes was 1.5-fold higher than for controls. A marked increase in p70S6K Thr(389) and rpS6 Ser-235/236 phosphorylation was observed concomitantly with an up-regulation of protein synthesis rate. Treatment with rapamycin prevented p70S6K phosphorylation and rescued cell size control in AMPK-deficient cells. Importantly, myotubes lacking AMPK were resistant to further cell size increase beyond AMPK deletion alone, as MyrAkt-induced hypertrophy was absent in these cells. Moreover, in skeletal muscle-specific deficient AMPKalpha1/alpha2 KO mice, soleus muscle showed a higher mass with myofibers of larger size and was associated with increased p70S6K and rpS6 phosphorylation. Our results uncover the role of AMPK in the maintenance of muscle cell size control and highlight the crosstalk between AMPK and mTOR/p70S6K signaling pathways coordinating a metabolic checkpoint on cell growth.
authors.affiliation: Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France.
authors.forename: Louise
authors.initials: L
authors.lastname: Lantier
authors.forename: Rémi
authors.initials: R
authors.lastname: Mounier
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Leclerc
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D048429:Cell Size; D002478:Cells, Cultured; D015151:Immunoblotting; D066298:In Vitro Techniques; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012265:Ribonucleotides / Q000494:pharmacology; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism
chemical_list: D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; C548179:Prkaa1 protein, mouse; C534978:Prkaa2 protein, mouse; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide