BACKGROUND: AMP-activated protein kinase (AMPK) regulatory gamma2 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 (TGgamma2N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic (alpha) and 2 regulatory (beta and gamma) subunits. Two alpha-subunit isoforms, alpha1 and alpha2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative alpha2 subunit of AMPK (TGalpha2DN) provide a tool for selectively inhibiting alpha2, but not alpha1, subunit-associated AMPK activity. METHODS AND RESULTS: In compound-heterozygous TGgamma2N488I/TGalpha2DN mice, AMPK activity associated with alpha2 but not alpha1 was decreased compared with TGgamma2N488I. The TGalpha2DN transgene reduced the disease phenotype of TGgamma2N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TGgamma2N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TGgamma2N488I 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 alpha2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the alpha2 rather than the alpha1 subunit are the primary mediators of the effects of PRKAG2 mutations.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)