AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation

Roselle Gélinas, Florence Mailleux, Justine Dontaine, Laurent Bultot, Bénédicte Demeulder, Audrey Ginion, Evangelos P. Daskalopoulos, Hrag Esfahani, Emilie Dubois-Deruy, Benjamin Lauzier, Chantal Gauthier, Aaron K. Olson, Bertrand Bouchard, Christine Des Rosiers, Benoit Viollet, Kei Sakamoto, Jean-Luc Balligand, Jean-Louis Vanoverschelde, Christophe Beauloye, Sandrine Horman and Luc Bertrand ()
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Roselle Gélinas: Université catholique de Louvain
Florence Mailleux: Université catholique de Louvain
Justine Dontaine: Université catholique de Louvain
Laurent Bultot: Université catholique de Louvain
Bénédicte Demeulder: Université catholique de Louvain
Audrey Ginion: Université catholique de Louvain
Evangelos P. Daskalopoulos: Université catholique de Louvain
Hrag Esfahani: Université catholique de Louvain
Emilie Dubois-Deruy: Université catholique de Louvain
Benjamin Lauzier: Univ. Nantes
Chantal Gauthier: Univ. Nantes
Aaron K. Olson: University of Washington School of Medicine and Seattle Children’s Research Institute
Bertrand Bouchard: Montreal Heart Institute
Christine Des Rosiers: Montreal Heart Institute
Benoit Viollet: Institut Cochin, INSERM U1016
Kei Sakamoto: Nestlé Institute of Health Sciences SA
Jean-Luc Balligand: Université catholique de Louvain
Jean-Louis Vanoverschelde: Université catholique de Louvain
Christophe Beauloye: Université catholique de Louvain
Sandrine Horman: Université catholique de Louvain
Luc Bertrand: Université catholique de Louvain

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract AMP-activated protein kinase (AMPK) has been shown to inhibit cardiac hypertrophy. Here, we show that submaximal AMPK activation blocks cardiomyocyte hypertrophy without affecting downstream targets previously suggested to be involved, such as p70 ribosomal S6 protein kinase, calcineurin/nuclear factor of activated T cells (NFAT) and extracellular signal-regulated kinases. Instead, cardiomyocyte hypertrophy is accompanied by increased protein O-GlcNAcylation, which is reversed by AMPK activation. Decreasing O-GlcNAcylation by inhibitors of the glutamine:fructose-6-phosphate aminotransferase (GFAT), blocks cardiomyocyte hypertrophy, mimicking AMPK activation. Conversely, O-GlcNAcylation-inducing agents counteract the anti-hypertrophic effect of AMPK. In vivo, AMPK activation prevents myocardial hypertrophy and the concomitant rise of O-GlcNAcylation in wild-type but not in AMPKα2-deficient mice. Treatment of wild-type mice with O-GlcNAcylation-inducing agents reverses AMPK action. Finally, we demonstrate that AMPK inhibits O-GlcNAcylation by mainly controlling GFAT phosphorylation, thereby reducing O-GlcNAcylation of proteins such as troponin T. We conclude that AMPK activation prevents cardiac hypertrophy predominantly by inhibiting O-GlcNAcylation.

Date: 2018
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DOI: 10.1038/s41467-017-02795-4

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