Important role for AMPKalpha1 in limiting skeletal muscle cell hypertrophy.
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.
Mounier
Rémi
R
INSERM U567, Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), 75014 Paris, France.
Lantier
Louise
L
Leclerc
Jocelyne
J
Sotiropoulos
Athanassia
A
Pende
Mario
M
Daegelen
Dominique
D
Sakamoto
Kei
K
Foretz
Marc
M
Viollet
Benoit
B
D055372:AMP-Activated Protein Kinases / Q000172:deficiency / Q000502:physiology*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D049108:Cell Enlargement; D006984:Hypertrophy; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology*; D020652:Peptide Elongation Factor 2 / Q000378:metabolism; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D020011:Protective Agents; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D058570:TOR Serine-Threonine Kinases
D002352:Carrier Proteins; D020652:Peptide Elongation Factor 2; D020011:Protective Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases