Activation of cardiac hypertrophic signaling pathways in a transgenic mouse with the human PRKAG2 Thr400Asn mutation

AbstractHuman mutations in PRKAG2, the gene encoding the γ2 subunit of AMP activated protein kinase (AMPK), cause a glycogen storage cardiomyopathy. In a transgenic mouse with cardiac specific expression of the Thr400Asn mutation in PRKAG2 (TGT400N), we previously reported initial cardiac hypertrophy (ages 2–8 weeks) followed by dilation and failure (ages 12–20 weeks). We sought to elucidate the molecular mechanisms of cardiac hypertrophy. TGT400N mice showed significantly increased cardiac mass/body mass ratios up to ∼3-fold beginning at age 2 weeks. Cardiac expression of ANP and BNP were ∼2- and ∼5-fold higher, respectively, in TGT400N relative to wildtype (WT) mice at age 2 weeks. NF-κB activity and nuclear translocation of the p50 subunit were increased ∼2- to 3-fold in TGT400N hearts relative to WT during the hypertrophic phase. Phosphorylated Akt and p70S6K were elevated ∼2-fold as early as age 2 weeks. To ascertain whether these changes in TGT400N mice were a consequence of increased AMPK activity, we crossbred TGT400N with TGα2DN mice, which express a dominant negative, kinase dead mutant of the AMPK α2 catalytic subunit and have low myocardial AMPK activity. Genetic reversal of AMPK overactivity led to a reduction in hypertrophy, nuclear translocation of NF-κB, phosphorylated Akt, and p70S6K. We conclude that inappropriate activation of AMPK secondary to the T400N PRKAG2 mutation is associated with the early activation of NF-κB and Akt signaling pathway, which mediates cardiac hypertrophy