Coordinated maintenance of muscle cell size control by AMP-activated protein kinase

• Published in: The FASEB journal 2010-09, Vol.24 (9), p.3555-3561
• Main Authors: Lantier, Louise, Mounier, Rémi, Leclerc, Jocelyne, Pende, Mario, Foretz, Marc, Viollet, Benoit
• Format: Article
• Language: English
• Subjects: Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Cell Size; Cells, Cultured; Immunoblotting; In Vitro Techniques; knockout mice; Metformin - pharmacology; Mice; Mice, Knockout; mTOR‐p70S6K signaling; Muscle Fibers, Skeletal - metabolism; muscle protein synthesis pathway; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Phosphorylation - drug effects; Ribonucleotides - pharmacology; Ribosomal Protein S6 Kinases, 70-kDa - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.10-155994

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 Thr³⁸⁹ 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 AMPKα1/α2 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.--Lantier, L., Mounier, R., Leclerc, J., Pende, M., Foretz, M., Viollet, B. Coordinated maintenance of muscle cell size control by AMP-activated protein kinase.