title: A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia.
abstract: Dominant mutations in the gamma2 regulatory subunit of AMP-activated protein kinase (AMPK), encoded by the gene PRKAG2, cause glycogen storage cardiomyopathy. We sought to elucidate the effect of the Thr400Asn (T400N) human mutation in a transgenic mouse (TGT400N) on AMPK activity, and its ability to protect the heart against ischemia-reperfusion injury. TGT400N hearts had markedly vacuolated myocytes, excessive accumulation of glycogen, hypertrophy, and preexcitation. Early activation of myocardial AMPK, followed by depression, and then recovery to wild-type levels was observed. AMPK activity correlated inversely with glycogen content. Partial rescue of the phenotype was observed when TGT400N mice were crossbred with TGalpha2DN mice, which overexpress a dominant negative mutant of the AMPK alpha2 catalytic subunit. TGT400N hearts had greater infarct sizes and apoptosis when subjected to ischemia-reperfusion. Increased AMPK activity is responsible for glycogen storage cardiomyopathy. Despite high glycogen content, the TGT400N heart is not protected against ischemia-reperfusion injury.
authors.affiliation: Cardiovascular Institute, Department of Medicine, University of Pittsburgh, S558, Pittsburgh, PA 15213, USA.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Banerjee
authors.forename: Ravi
authors.initials: R
authors.lastname: Ramani
authors.forename: Samir
authors.initials: S
authors.lastname: Saba
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rager
authors.forename: Rong
authors.initials: R
authors.lastname: Tian
authors.forename: Michael A
authors.initials: MA
authors.lastname: Mathier
authors.forename: Ferhaan
authors.initials: F
authors.lastname: Ahmad
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D002316:Cardiotonic Agents; D004789:Enzyme Activation; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002316:Cardiotonic Agents; D009097:Multienzyme Complexes; D006003:Glycogen; C526181:PRKAA2 protein, human; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases