Important role for AMPKα1 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 AMPK alpha 1 catalytic subunit on muscle cell size control and adaptation to muscle hypertrophy. We found that AMPK alpha 1(-/-) 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 AMPK alpha 1(-/-) and control mice to mechanical overloading to induce muscle hypertrophy. We observed significant elevations of AMPK alpha 1 activity in the control muscle at days 7 and 21 after the overload. Overloading-induced muscle hypertrophy was significantly accelerated in AMPK alpha 1(-/-) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control AMPK alpha 1(-/-) mice, respectively]. This enhanced growth of AMPK alpha 1-deficient muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPK alpha 1 plays an important role in limiting skeletal muscle overgrowth during hypertrophy through inhibition of the mTOR-signaling pathway. Mounier, R., Louise Lantier, Leclerc, J., Sotiropoulos, A., Pende, M., Daegelen, D., Sakamoto, K., Foretz, M., Viollet, B. Important role for AMPK alpha 1 in limiting skeletal muscle cell hypertrophy. FASEB J. 23, 2264-2273 (2009)