Increased α2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy

Background: AMP-activated protein kinase (AMPK) regulatory gamma 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 (TG gamma 2(N488I)). AMPK is a heterotrimeric kinase consisting of 1 catalytic (alpha) and 2 regulatory (beta and gamma) subunits. Two alpha-subunit isoforms, alpha 1 and alpha 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 alpha 2 subunit of AMPK (TG alpha 2(DN)) provide a tool for selectively inhibiting alpha 2, but not alpha 1, subunit-associated AMPK activity. Methods and Results: In compound-heterozygous TG gamma 2(N488I)/TG alpha 2(DN) mice, AMPK activity associated with alpha 2 but not alpha 1 was decreased compared with TG gamma 2N(488I). The TG alpha 2DN transgene reduced the disease phenotype of TG gamma 2(N488I), partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TG gamma 2(N488I) hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TG gamma 2(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 alpha 2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the alpha 2 rather than the alpha 1 subunit are the primary mediators of the effects of PRKAG2 mutations.