Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen

Circ Cardiovasc Genet. 2009 Oct;2(5):457-66. doi: 10.1161/CIRCGENETICS.108.834564. Epub 2009 Jul 15.


Background: Humans with an R302Q mutation in AMPKgamma(2) (the PRKAG2 gene) develop a glycogen storage cardiomyopathy characterized by a familial form of Wolff-Parkinson-White syndrome and cardiac hypertrophy. This phenotype is recapitulated in transgenic mice with cardiomyocyte-restricted expression of AMPKgamma(2)R302Q. Although considerable information is known regarding the consequences of harboring the gamma(2)R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy.

Methods and results: To distinguish the direct effects of gamma(2)R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPKgamma(2) subunit (TGgamma(2)WT) or the mutated form (TGgamma(2)R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content, AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, gamma(2)WT expression has similar, yet less marked effects than gamma(2)R302Q expression in both cardiomyocytes and hearts.

Conclusions: Using acute and chronic models of gamma(2)R302Q expression, we have differentiated the direct effects of the gamma(2)R302Q mutation from eventual compensatory modifications. Our data suggest that expression of gamma(2)R302Q induces AMPK activation and the eventual increase in glycogen content, a finding that is masked in hearts from transgenic adult mice. These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / genetics*
  • AMP-Activated Protein Kinases / metabolism
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • Gene Expression*
  • Glycogen / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation, Missense*
  • Myocytes, Cardiac / metabolism*
  • Rats
  • Signal Transduction*
  • Wolff-Parkinson-White Syndrome / enzymology*
  • Wolff-Parkinson-White Syndrome / genetics


  • Glycogen
  • PRKAG2 protein, human
  • AMP-Activated Protein Kinases