Abstract 73: Aberrant Activation of γ2-AMPK Increases Cardiac Growth Through Cellular Hypertrophy and Hyperplasia
AMP-activated protein kinase (AMPK) is an energy sensor and a key regulator of cell metabolism, hence a promising drug target. Point mutations in the regulatory γ2-subunit (encoded by PRKAG2 gene) have been shown to cause a unique form of cardiomyopathy in humans characterized by cardiac growth, arrhythmias and glycogen storage. In previous studies, we demonstrated that the mutation of prkag2 (N488I) caused aberrant activation of AMPK leading to glycogen storage. However, elimination of glycogen storage by inhibiting glycogen synthase activity failed to normalize heart weight (HW) of the mutant mice. Here, we aimed to determine whether cardiac growth in PRKAG2 ardiomyopathy was dueto cellular hypertrophy or hyperplasia. We used transgenic mice expressing a mutant PRKAG2 (N488I) in the heart (TGγ2N488I) that faithfully recapitulated PRKAG2 cardiomyopathy. We determined HW and cardiac myocyte size in adult (2 months) and postnatal (2 weeks) hearts in WT and TGγ2N488I. At 2 months, TGγ2N488I hearts show a 2.4-fold increase in HW/BW (body weight) (10.3 ± 1.44 vs. 4.3± 0.17 mg/g) as well as cross-sectional cell surface area compared WT hearts (325 ± 13 vs. 155 ± 5.4 μm2,p<0.01), suggesting cellular hypertrophy in adult TGγ2N488I heart. Furthermore, we observed increased mTOR activity evidenced by enhanced phosphorylation of mTOR (Ser2448) as well as its downstream targets S6 and 4E-BP. The HW of TGγ2N488I was partially inhibited by treatment with rapamycin, an inhibitor of mTOR. Interestingly, the length and width of isolated cardiomyocytes from 2 weeks old mice were not different between the WT and TGγ2N488I heart in spite of a 50% increase of HW of TGγ2N488I mice. We observed a 2- fold increase in the expression of a proliferation marker, proliferating cell nuclear antigen (PCNA) during postnatal cardiac growth. Expression of Cyclin genes including cyclin D1, D2 and E1 was greatly increased in TGγ2N488I hearts (2.4 - 4 fold, p<0.01 vs. WT). Taken together, these data indicate that aberrant γ2-AMPK activation stimulates cardiac growth through increased cell number during postnatal growth period and increased cell size at adulthood. These results suggest a novel role of γ2-AMPK in the growth of cardiac myocytes.
- © 2012 by American Heart Association, Inc.