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(Circulation. 2005;112:3140-3148.)
© 2005 American Heart Association, Inc.

Heart Failure

Increased 2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy

Ferhaan Ahmad, MD, PhD^*; Michael Arad, MD^*; Nicolas Musi, MD; Huamei He, MD, PhD; Cordula Wolf, MD; Dorothy Branco, BS; Antonio R. Perez-Atayde, MD; David Stapleton, PhD; Deeksha Bali, PhD; Yanqiu Xing, PhD; Rong Tian, MD, PhD; Laurie J. Goodyear, PhD; Charles I. Berul, MD; Joanne S. Ingwall, PhD; Christine E. Seidman, MD; J.G. Seidman, PhD

From the Department of Genetics (F.A., M.A., C.E.S., J.G.S.), Harvard Medical School and Howard Hughes Medical Institute, Boston, Mass; Cardiovascular Institute (F.A.), Department of Medicine, and Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pa; Heart Institute (M.A.), Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Research Division (N.M., L.J.G.), Joslin Diabetes Center, Boston, Mass; NMR Laboratory for Physiological Chemistry (H.H., Y.X., R.T., J.S.I.), Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Mass; Department of Cardiology (C.W., D. Branco, C.I.B.), Children’s Hospital, Boston, Mass; Department of Pathology (A.R.P.-A.), Children’s Hospital, Boston, Mass; Bio21 Molecular Science and Biotechnology Institute (D.S.), University of Melbourne, Melbourne, Australia; Pediatric Medical Genetics (D. Bali), Duke University Medical Center, Research Triangle Park, NC; and Cardiovascular Division (C.E.S.), Brigham and Women’s Hospital, Boston, Mass.

Correspondence to J.G. Seidman, PhD, Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, NRB 256, Boston, MA 02115. E-mail seidman{at}genetics.med.harvard.edu

Received March 25, 2005; revision received August 23, 2005; accepted September 12, 2005.

Background— AMP-activated protein kinase (AMPK) regulatory 2 subunit (PRKAG2) mutations cause a human cardiomyopathy with cardiac hypertrophy, preexcitation, and glycogen deposition. PRKAG2 cardiomyopathy is recapitulated in transgenic mice overexpressing mutant PRKAG2 N488I in the heart (TG2^N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic () and 2 regulatory (ß and ) subunits. Two -subunit isoforms, 1 and 2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative 2 subunit of AMPK (TG2^DN) provide a tool for selectively inhibiting 2, but not 1, subunit-associated AMPK activity.

Methods and Results— In compound-heterozygous TG2^N488I/TG2^DN mice, AMPK activity associated with 2 but not 1 was decreased compared with TG2^N488I. The TG2^DN transgene reduced the disease phenotype of TG2^N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TG2^N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TG2^N488I mice after exercise stress, indicating availability of the stored glycogen for metabolic utilization. No differences in glycogen-metabolizing enzymes were observed.

Conclusions— The PRKAG2 N488I mutation causes inappropriate AMPK activation, which leads to glycogen accumulation and conduction system disease. The accumulated glycogen can serve as an energy source, and the animals have contractile reserve during exercise. Because the dominant-negative 2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the 2 rather than the 1 subunit are the primary mediators of the effects of PRKAG2 mutations.

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