Important role for AMPKαl in limiting skeletal muscle cell hypertrophy

• DOI: 10.1096/fj.08-119057
• Publication Date: 2009-02-24T01:34:19Z
• Authors: Rémi Mounier; Louise Lantier; Jocelyne Leclerc; Athanassia Sotiro...; Mario Pende; Dominique Daegelen; Kei Sakamoto; Marc Foretz; Benoit Viollet
• Keywords: MESH: Signal Transduction; protein synthesis; MESH: Protective Agents; MESH: Carrier Proteins; AMP-Activated Protein Kinases; Cell Enlargement; Protective Agents; MESH: Mice, Knockout; mTOR-S6K signaling; Mice; 03 medical and health sciences; muscle functional overload; Peptide Elongation Factor 2; [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO]; Animals; MESH: Animals; MESH: Peptide Elongation Factor 2; MESH: AMP-Activated Protein Kinases; Phosphorylation; Muscle, Skeletal; MESH: Mice; MESH: TOR Serine-Threonine Kinases; MESH: Cell Enlargement; Mice, Knockout; MESH: Muscle, Skeletal; 0303 health sciences; MESH: Stress, Mechanical; MESH: Hypertrophy; MESH: Phosphorylation; MESH: Proto-Oncogene Proteins c-akt; TOR Serine-Threonine Kinases; Muscle functional overload; Hypertrophy; [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism; MESH: Phosphotransferases (Alcohol Group Acceptor); Phosphotransferases (Alcohol Group Acceptor); Stress, Mechanical; Protein synthesis; Carrier Proteins; Proto-Oncogene Proteins c-akt; Signal Transduction

Activation of AMP-activated protein kinase (AMPK) inhibits protein synthesis through the suppression of the mammalian target of rapamycin complex 1 (mTORC1), a critical regulator of muscle growth. The purpose of this investigation was to determine the role of the AMPKalpha1 catalytic subunit on muscle cell size control and adaptation to muscle hypertrophy. We found that AMPKalpha1(-/-) primary cultured myotubes and myofibers exhibit larger cell size compared with control cells in response to chronic Akt activation. We next subjected the plantaris muscle of AMPKalpha1(-/-) and control mice to mechanical overloading to induce muscle hypertrophy. We observed significant elevations of AMPKalpha1 activity in the control muscle at days 7 and 21 after the overload. Overloading-induced muscle hypertrophy was significantly accelerated in AMPKalpha1(-/-) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control vs. AMPKalpha1(-/-) mice, respectively]. This enhanced growth of AMPKalpha1-deficient muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPKalpha1 plays an important role in limiting skeletal muscle overgrowth during hypertrophy through inhibition of the mTOR-signaling pathway.