Background— AMP-activated protein kinase (AMPK) regulatory γ2 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 (TGγ2^N488I). AMPK is a heterotrimeric kinase consisting of 1 catalytic (α) and 2 regulatory (β and γ) subunits. Two α-subunit isoforms, α1 and α2, are expressed in the heart; however, the contribution of AMPK utilization of these subunits to PRKAG2 cardiomyopathy is unknown. Mice overexpressing a dominant-negative α2 subunit of AMPK (TGα2^DN) provide a tool for selectively inhibiting α2, but not α1, subunit-associated AMPK activity.

Methods and Results— In compound-heterozygous TGγ2^N488I/TGα2^DN mice, AMPK activity associated with α2 but not α1 was decreased compared with TGγ2^N488I. The TGα2^DN transgene reduced the disease phenotype of TGγ2^N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TGγ2^N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TGγ2^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 α2 subunit attenuates the mutant PRKAG2 phenotype, AMPK complexes containing the α2 rather than the α1 subunit are the primary mediators of the effects of PRKAG2 mutations.