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Important role for AMPK1 in limiting skeletal muscle cell hypertrophy

Rémi Mounier^*,, Louise Lantier^*,, Jocelyne Leclerc^*,, Athanassia Sotiropoulos^*,, Mario Pende^,, Dominique Daegelen^*,, Kei Sakamoto^||, Marc Foretz^*, and Benoit Viollet^*,,1

^* Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France;

INSERM, U567, Paris, France;

INSERM, U845, Paris, France;

Université Paris Descartes, UMRS 845, Paris, France;

^|| Medical Research Council, Protein Phosphorylation Unit, College of Life Sciences, University of Dundee, Dundee, UK

¹ Correspondence: INSERM U567, Institut Cochin, Département Endocrinologie, Métabolisme et Cancer, 24, rue du Faubourg St.-Jacques, 75014 Paris, France. E-mail: benoit.viollet{at}inserm.fr

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 AMPK1 catalytic subunit on muscle cell size control and adaptation to muscle hypertrophy. We found that AMPK1(–/–) 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 AMPK1(–/–) and control mice to mechanical overloading to induce muscle hypertrophy. We observed significant elevations of AMPK1 activity in the control muscle at days 7 and 21 after the overload. Overloading-induced muscle hypertrophy was significantly accelerated in AMPK1(–/–) mice than in control mice [+32 vs. +53% at day 7 and +57 vs. +76% at day 21 in control vs. AMPK1(–/–) mice, respectively]. This enhanced growth of AMPK1-deficient muscle was accompanied by increased phosphorylation of mTOR signaling downstream targets and decreased phosphorylation of eukaryotic elongation factor 2. These results demonstrate that AMPK1 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 AMPK1 in limiting skeletal muscle cell hypertrophy.

Key Words: muscle functional overload • protein synthesis • mTOR-S6K signaling

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