title: Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model.
abstract: BACKGROUND
  The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome.
  
  
  METHODS
  Myocardial and skeletal muscle glucose uptake was assessed with 2-[18F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings.
  
  
  RESULTS
  TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes.
  
  
  CONCLUSIONS
  These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients.
authors.affiliation: National Cardiac PET Centre, Division of Cardiology, University of Ottawa Heart Institute, 40 Ruskin St, Ottawa, Ontario K1Y 4W7, Canada. jdasilva@ottawaheart.ca.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Thorn
authors.forename: Michael H
authors.initials: MH
authors.lastname: Gollob
authors.forename: Mary-Ellen
authors.initials: ME
authors.lastname: Harper
authors.forename: Rob S
authors.initials: RS
authors.lastname: Beanlands
authors.forename: Robert A
authors.initials: RA
authors.lastname: Dekemp
authors.forename: Jean N
authors.initials: JN
authors.lastname: Dasilva