Mutation in the γ2-subunit of AMPK Stimulates Cardiomyocyte Proliferation and Hypertrophy Independent of Glycogen Storage

Rationale: AMP-activated protein kinase (AMPK) is a master regulator of cell metabolism and an attractive drug target for cancer, metabolic and cardiovascular diseases. Point mutations in the regulatory γ2-subunit of AMPK (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular pre-excitation and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the utility of AMPK as a drug target. Objective: We sought to identify the pro-growth signaling pathway(s) triggered by Prkag2 mutation and to distinguish it from the secondary response to glycogen storage. Methods and Results: : In a mouse model of N488I mutation of the Prkag2 (R2M), we rescued the glycogen storage phenotype by genetic inhibition of glucose-6-phosphate stimulated glycogen synthase activity. Ablation of glycogen storage eliminated the ventricular pre-excitation but did not affect the excessive cardiac growth in R2M mice. The pro-growth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mTOR and inactivation of FoxO signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mTOR activity by rapamycin or restoration of FoxO activity by overexpressing FoxO1 rescued the abnormal cardiac growth. Conclusions: Our study reveals a novel mechanism for Prkag2 cardiomyopathy independent of glycogen storage. The role of γ2-AMPK in cell growth also has broad implications in cardiac development, growth and regeneration.