TY - JOUR

T1 - AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation

AU - Gélinas, Roselle

AU - Mailleux, Florence

AU - Dontaine, Justine

AU - Bultot, Laurent

AU - Demeulder, Bénédicte

AU - Ginion, Audrey

AU - Daskalopoulos, Evangelos P.

AU - Esfahani, Hrag

AU - Dubois-Deruy, Emilie

AU - Lauzier, Benjamin

AU - Gauthier, Chantal

AU - Olson, Aaron K.

AU - Bouchard, Bertrand

AU - Des Rosiers, Christine

AU - Viollet, Benoit

AU - Sakamoto, Kei

AU - Balligand, Jean Luc

AU - Vanoverschelde, Jean Louis

AU - Beauloye, Christophe

AU - Horman, Sandrine

AU - Bertrand, Luc

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85041048743&partnerID=8YFLogxK

U2 - 10.1038/s41467-017-02795-4

DO - 10.1038/s41467-017-02795-4

M3 - Journal article

C2 - 29371602

AN - SCOPUS:85041048743

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 374

ER -