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

Karalyn D. Folmes, Anita Y.M. Chan, Debby P.Y. Koonen, Thomas C. Pulinilkunnil, István Baczkó, Beth E. Hunter, Stephanie Thorn, Michael F. Allard, Robert Roberts, Michael H. Gollob, Peter E. Light, Jason R.B. Dyck

Research output: Article

23 Citations (Scopus)


Background-Humans with an R302Q mutation in AMPKγ2 (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 AMPKγ2R302Q. Although considerable information is known regarding the consequences of harboring the γ2R302Q 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 γ2R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPKγ2 subunit (TGγ2WT) or the mutated form (TGγ2R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of γ2R302Q 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 TGγ2R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, γ2WT expression has similar, yet less marked effects than γ2R302Q expression in both cardiomyocytes and hearts. Conclusions-Using acute and chronic models of γ2R302Q expression, we have differentiated the direct effects of the γ2R302Q mutation from eventual compensatory modifications. Our data suggest that expression of γ2R302Q 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.

Original languageEnglish
Pages (from-to)457-466
Number of pages10
JournalCirculation: Cardiovascular Genetics
Issue number5
Publication statusPublished - okt. 1 2009


ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

Folmes, K. D., Chan, A. Y. M., Koonen, D. P. Y., Pulinilkunnil, T. C., Baczkó, I., Hunter, B. E., Thorn, S., Allard, M. F., Roberts, R., Gollob, M. H., Light, P. E., & Dyck, J. R. B. (2009). Distinct early signaling events resulting from the expression of the PRKAG2 R302Q mutant of AMPK contribute to increased myocardial glycogen. Circulation: Cardiovascular Genetics, 2(5), 457-466. https://doi.org/10.1161/CIRCGENETICS.108.834564