title: Increased alpha2 subunit-associated AMPK activity and PRKAG2 cardiomyopathy.
abstract: 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.
  
  
  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.
authors.affiliation: Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute, Boston, MA, USA.
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
authors.forename: Michael
authors.initials: M
authors.lastname: Arad
authors.forename: Nicolas
authors.initials: N
authors.lastname: Musi
authors.forename: Huamei
authors.initials: H
authors.lastname: He
authors.forename: Cordula
authors.initials: C
authors.lastname: Wolf
authors.forename: Dorothy
authors.initials: D
authors.lastname: Branco
authors.forename: Antonio R
authors.initials: AR
authors.lastname: Perez-Atayde
authors.forename: David
authors.initials: D
authors.lastname: Stapleton
authors.forename: Deeksha
authors.initials: D
authors.lastname: Bali
authors.forename: Yanqiu
authors.initials: Y
authors.lastname: Xing
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.forename: Charles I
authors.initials: CI
authors.lastname: Berul
authors.forename: Joanne S
authors.initials: JS
authors.lastname: Ingwall
authors.forename: Christine E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D019943:Amino Acid Substitution; D000818:Animals; D009202:Cardiomyopathies / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D005080:Exercise Test; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D011494:Protein Kinases / Q000235:genetics* / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D021122:Protein Subunits; D011494:Protein Kinases; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human