Abstract 16614: Reduced Glucose Uptake and Increased Glycogen Synthase is Observed Early in a Mouse Model of the Human Arg302Gln-PRKAG2 Cardiac Syndrome
Background: The PRKAG2 cardiac syndrome is characterized by frequent heart arrhythmias, excessive cardiac glycogen deposition and cardiomyopathy due to a mutation in the gamma2 subunit of AMP-activated kinase (AMPK). To further study the pathogenesis of this disease, we have produced an AMPK gamma2 transgenic mutant mouse model (TGmut). FDG PET glucose uptake was correlated to alterations in the glucose metabolism pathway and compared to control mice expressing the human wildtype AMPK (TGwt) to investigate the underlying glycogen storage disease.
Methods: Test- retest was conducted with n=6 normal, fed FVB mice with blood curves derived from the abdominal vena cava to determine glucose uptake with Patlak analysis. Coefficient of variation was determined for population variability. These methods were applied to n=6 affected TGmut and n=4 TGwt controls. FDG PET was correlated with echocardiography and protein expression of GLUT4 ,glycogen synthase (GS), GS phophorylase (GSP), glycogen synthase kinase (GSK), and phosphorylated GSK (GSKP) and cardiac glycogen deposition.
Results: Global LV Ki had a mean ± SD of 1.10 ± 0.22 corresponding to a population variability of 20%. In the PRKAG2 mouse model there was a ∼60% decrease in global FDG uptake in TGmut mice compared to TGwt controls (p<0.001) with an increase in LV wall thickness as measured by echocardiography (p<0.05). This correlates with a decrease in GLUT4 expression of ∼40% compared to TGwt mice (p<0.05). GS is significantly increased in TGmut 40% (p<0.05) with a trend towards a 20% increase in GSP. There was a 60% reduction in GSKP (p<0.05) with no change in GSK levels and cardiac glycogen stores increased (p<0.05).
Conclusions: Our findings further suggest that the mutation in AMPK correlates with a reduction in GSK phosphorylation, reducing the inhibition on GS expression and increasing glycogen deposition. Increased cardiac glycogen deposition results in increased LV wall thickness and decreased glucose uptake as early as 1 month of age in the TGmut mice. This study indicates that at a very early age, glucose uptake is decreased with glycogen forming pathways increased in the PRKAG2 mouse model and pharmacological metabolic modulation may need to occur prior to development of disease morbidity.
- © 2011 by American Heart Association, Inc.