AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation
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AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. / Gélinas, Roselle; Mailleux, Florence; Dontaine, Justine; Bultot, Laurent; Demeulder, Bénédicte; Ginion, Audrey; Daskalopoulos, Evangelos P.; Esfahani, Hrag; Dubois-Deruy, Emilie; Lauzier, Benjamin; Gauthier, Chantal; Olson, Aaron K.; Bouchard, Bertrand; Des Rosiers, Christine; Viollet, Benoit; Sakamoto, Kei; Balligand, Jean Luc; Vanoverschelde, Jean Louis; Beauloye, Christophe; Horman, Sandrine; Bertrand, Luc.
I: Nature Communications, Bind 9, Nr. 1, 374, 01.12.2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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 -
ID: 238434139