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Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy.

Publication ,  Journal Article
Ahmad, F; Arad, M; Musi, N; He, H; Wolf, C; Branco, D; Perez-Atayde, AR; Stapleton, D; Bali, D; Xing, Y; Tian, R; Goodyear, LJ; Berul, CI ...
Published in: Circulation
November 15, 2005

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.

Duke Scholars

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 15, 2005

Volume

112

Issue

20

Start / End Page

3140 / 3148

Location

United States

Related Subject Headings

  • Protein Subunits
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Mutation, Missense
  • Multienzyme Complexes
  • Mice, Transgenic
  • Mice
  • Humans
  • Exercise Test
  • Echocardiography
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Ahmad, F., Arad, M., Musi, N., He, H., Wolf, C., Branco, D., … Seidman, J. G. (2005). Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation, 112(20), 3140–3148. https://doi.org/10.1161/CIRCULATIONAHA.105.550806
Ahmad, Ferhaan, Michael Arad, Nicolas Musi, Huamei He, Cordula Wolf, Dorothy Branco, Antonio R. Perez-Atayde, et al. “Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy.Circulation 112, no. 20 (November 15, 2005): 3140–48. https://doi.org/10.1161/CIRCULATIONAHA.105.550806.
Ahmad F, Arad M, Musi N, He H, Wolf C, Branco D, et al. Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation. 2005 Nov 15;112(20):3140–8.
Ahmad, Ferhaan, et al. “Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy.Circulation, vol. 112, no. 20, Nov. 2005, pp. 3140–48. Pubmed, doi:10.1161/CIRCULATIONAHA.105.550806.
Ahmad F, Arad M, Musi N, He H, Wolf C, Branco D, Perez-Atayde AR, Stapleton D, Bali D, Xing Y, Tian R, Goodyear LJ, Berul CI, Ingwall JS, Seidman CE, Seidman JG. Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy. Circulation. 2005 Nov 15;112(20):3140–3148.

Published In

Circulation

DOI

EISSN

1524-4539

Publication Date

November 15, 2005

Volume

112

Issue

20

Start / End Page

3140 / 3148

Location

United States

Related Subject Headings

  • Protein Subunits
  • Protein Serine-Threonine Kinases
  • Protein Kinases
  • Mutation, Missense
  • Multienzyme Complexes
  • Mice, Transgenic
  • Mice
  • Humans
  • Exercise Test
  • Echocardiography