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Original Articles

Distinct Early Signaling Events Resulting From the Expression of the PRKAG2 R302Q Mutant of AMPK Contribute to Increased Myocardial Glycogen

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

From the Cardiovascular Research Centre (K.D.F., A.Y.M.C., D.P.Y.K., T.C.P., I.B., B.E.H., P.E.L., J.R.B.D.), Departments of Pediatrics (D.P.Y.K., T.C.P., J.R.B.D.) and Pharmacology (K.D.F., A.Y.M.C., I.B., B.E.H., P.E.L., J.R.B.D.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada; University of Ottawa Heart Institute (S.T., M.H.G., R.R.), Ottawa, Ontario, Canada; and James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology and Laboratory Medicine (M.F.A.), University of British Columbia-St Paul’s Hospital, Vancouver, British Columbia, Canada.

Correspondence to Jason R.B. Dyck, PhD, 450 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. E-mail jason.dyck{at}ualberta.ca

Received November 10, 2008; accepted June 17, 2009.

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. Although 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— To distinguish the direct effects of ₂R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPK₂ subunit (TG₂WT) or the mutated form (TG₂R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of ₂R302Q 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 TG₂R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, ₂WT expression has similar, yet less marked effects than ₂R302Q expression in both cardiomyocytes and hearts.

Conclusions— Using acute and chronic models of ₂R302Q expression, we have differentiated the direct effects of the ₂R302Q 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 the PRKAG2 R302Q mutation on cardiac metabolic signaling events.

Key Words: glycogen • molecular biology • signal transduction • AMPK

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CLINICAL PERSPECTIVE

Drs Folmes and Chan contributed equally to this work.