AMPK Activation Counteracts Cardiac Hypertrophy by Reducing O-GlcNAcylation

Nat Commun. 2018 Jan 25;9(1):374. doi: 10.1038/s41467-017-02795-4.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / deficiency
  • AMP-Activated Protein Kinases / genetics*
  • Acetylglucosamine / metabolism*
  • Acetylglucosamine / pharmacology
  • Acylation / drug effects
  • Animals
  • Animals, Newborn
  • Azaserine / pharmacology
  • Azo Compounds / pharmacology
  • Cardiomegaly / genetics*
  • Cardiomegaly / metabolism
  • Cardiomegaly / pathology
  • Enzyme Activation / drug effects
  • Enzyme Activators / pharmacology
  • Gene Expression Regulation
  • Glycosylation / drug effects
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Heart Ventricles / pathology
  • Male
  • Mice
  • Mice, Knockout
  • Myocardium / metabolism*
  • Myocardium / pathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Nitrogenous Group Transferases / antagonists & inhibitors
  • Nitrogenous Group Transferases / genetics*
  • Nitrogenous Group Transferases / metabolism
  • Norleucine / analogs & derivatives
  • Norleucine / pharmacology
  • Phosphorylation / drug effects
  • Primary Cell Culture
  • Pyrones / pharmacology
  • Rats
  • Rats, Wistar
  • Signal Transduction
  • Thiophenes / pharmacology
  • Troponin T / genetics
  • Troponin T / metabolism

Substances

  • A 769662
  • Azo Compounds
  • Enzyme Activators
  • Pyrones
  • Thiophenes
  • Troponin T
  • Norleucine
  • Azaserine
  • Nitrogenous Group Transferases
  • Gfpt1 protein, mouse
  • AMPK alpha2 subunit, mouse
  • AMP-Activated Protein Kinases
  • 6-diazo-5-oxonorleucine
  • Acetylglucosamine