Published Online
on July 15, 2009

A more recent version of this article appeared on October 1, 2009

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Original Article

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

Karalyn D. Folmes¹; Anita Y.M. Chan¹; Debby P.Y. Koonen¹; Thomas C. Pulinilkunnil¹; István Baczkó¹; Beth E. Hunter¹; Stephanie Thorn²; Michael F. Allard³; Robert Roberts²; Michael H. Gollob²; Robert Roberts⁴; Peter E. Light¹ and Jason R.B. Dyck^1,5

¹ University of Alberta, Edmonton, Alberta, Canada;
² University of Ottawa Heart Institute, Ottawa, Ontario, Canada;
³ University of British Columbia–St Paul's Hospital, Vancouver, British Columbia, Canada;
⁴ University of Ottawa Heart Institute

⁵ E-mail: jason.dyck{at}ualberta.ca

Background—Humans with an R302Q mutation in AMPK₂ (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 AMPK₂R302Q. While considerable information is known regarding the consequences of harboring the ₂R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy.

Methods and Results—In order to distinguish the direct effects of ₂R302Q expression from later compensatory alterations in signaling, we utilized transgenic mice expressing either the wildtype AMPK₂ subunit (TG₂WT) or the mutated form (TG₂R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. While acute expression of ₂R302Q induces AMPK activation and upregulation of glycogen synthase (GS) and AS160, with an associated increase in glycogen content, AMPK activity, GS activity and AS160 expression are reduced in hearts from TG₂R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, ₂WT expression has similar, yet less dramatic effects than ₂R302Q expression in both cardiomyocytes and hearts.

Conclusions—Utilizing acute and chronic models of ₂R302Q expression, we have differentiated the direct effects of the AMPK₂R302Q mutation from eventual compensatory modifications. Our data suggest that expression of ₂R302Q 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 PRKAG2 mutations on cardiac metabolic signaling events.

Key Words: molecular biology • signal transduction • Wolff-Parkinson-White syndrome • AMP-activated protein kinase • Glycogen