AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation

Roselle Gélinas (1) , Florence Mailleux (1) , Justine Dontaine (1) , Laurent Bultot (1) , Bénédicte Demeulder (1) , Audrey Ginion (1) , Evangelos P. Daskalopoulos (1) , Hrag Esfahani , Emilie Dubois-Deruy (2) , Benjamin Lauzier (3) , Chantal Gauthier (3) , Aaron K. Olson , Bertrand Bouchard (4) , Christine Des Rosiers , Benoit Viollet (5, 6) , Kei Sakamoto (7) , Jean-Luc Balligand (2) , Jean-Louis Vanoverschelde (8, 9, 2, 10) , Christophe Beauloye (11) , Sandrine Horman (12) , Luc Bertrand (1)

1 UCL - Université Catholique de Louvain = Catholic University of Louvain
2 IREC - Institut de Recherche Expérimentale et Clinique
3 ITX - ITX - unité de recherche de l'institut du thorax
4 CEFE - Centre d’Ecologie Fonctionnelle et Evolutive
5 IC UM3 (UMR 8104 / U1016) - Institut Cochin
6 USPC - Université Sorbonne Paris Cité
7 Advanced Institute of Industrial Technology
8 MIRO - Pôle d’Imagerie Médicale, Radiothérapie et Oncologie
9 CARD - Pôle de Recherche Cardiovasculaire
10 Division of Cardiology
11 Pole of Cardiovascular Pathology and Cliniques Universitaires Saint-Luc
12 Division of cardiology

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.

Domaines: Sciences du Vivant [q-bio]

Roselle Gélinas, Florence Mailleux, Justine Dontaine, Laurent Bultot, Bénédicte Demeulder, et al.. AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. Nature Communications, 2018, 9 (1), pp.374. ⟨10.1038/s41467-017-02795-4⟩. ⟨hal-01833329⟩