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Increased α2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy
Journal article   Open access   Peer reviewed

Increased α2 Subunit–Associated AMPK Activity and PRKAG2 Cardiomyopathy

Ferhaan Ahmad, Michael Arad, Nicolas Musi, Huamei He, Cordula Wolf, Dorothy Branco, Antonio R Perez-Atayde, David Stapleton, Deeksha Bali, Yanqiu Xing, …
Circulation (New York, N.Y.), Vol.112(20), pp.3140-3148
11/15/2005
DOI: 10.1161/CIRCULATIONAHA.105.550806
PMID: 16275868
url
https://doi.org/10.1161/CIRCULATIONAHA.105.550806View
Published (Version of record) Open Access

Abstract

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 (TGγ2N488I). 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 (TGα2DN) provide a tool for selectively inhibiting α2, but not α1, subunit-associated AMPK activity. Methods and Results— In compound-heterozygous TGγ2N488I/TGα2DN mice, AMPK activity associated with α2 but not α1 was decreased compared with TGγ2N488I. The TGα2DN transgene reduced the disease phenotype of TGγ2N488I, partially or completely normalizing the ECG, cardiac function, cardiac morphology, and exercise capacity in compound-heterozygous mice. TGγ2N488I hearts had normal resting levels of high-energy phosphates and could improve cardiac performance during exercise. Cardiac glycogen content decreased in TGγ2N488I 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.
 Protein Kinases - metabolism Cardiomyopathies - diagnostic imaging Protein Kinases - genetics Echocardiography Humans Protein-Serine-Threonine Kinases - genetics Multienzyme Complexes - metabolism Mice, Transgenic Multienzyme Complexes - genetics Mutation, Missense AMP-Activated Protein Kinases Protein Subunits - metabolism Cardiomyopathies - genetics Cardiomyopathies - physiopathology Exercise Test Animals Mice Protein-Serine-Threonine Kinases - metabolism Amino Acid Substitution Disease Models, Animal Protein Subunits - genetics

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