Mutation in the γ2-Subunit of AMP-Activated Protein Kinase Stimulates Cardiomyocyte Proliferation and Hypertrophy Independent of Glycogen Storage

Abstract

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.

Activation of γ2-AMPK Suppresses Ribosome Biogenesis and Protects Against Myocardial Ischemia/Reperfusion Injury

“…AMPK also inactivates eukaryotic elongation factor-2 (eEF2), another important player in protein synthesis by activating eEF2 kinase. 33 In contrast to this well-established notion, both mTOR activity and S6 phosphorylation are increased in mouse models with predominant activation of γ2-AMPK 17, 34 suggesting that the AMPK effect on this pathway is dependent on the γ isoform. Here we demonstrate a distinct mechanism by which γ2-AMPK regulates protein synthesis via transient nuclear translocation and suppression of rRNA synthesis during acute stress.…”

Physiological Expression of AMPKγ2 Mutation Causes Wolff-Parkinson-White Syndrome and Induces Kidney Injury in Mice

“…Excessive cardiac growth and cardiomyopathy, however, persisted in AMPK␥2 NI transgenic mice, indicating a glycogen storage-independent and AMPK intrinsic activation mechanism on cell growth of cardiac myocytes. This effect was proposed to be mediated by enhanced insulin sensitivity and activation of the Akt-mTOR-FOXO3A pathway in cardiac myocytes (21). Interestingly, another mutation of AMPK␥2, R302Q, causes a reduction in AMPK activity yet exhibits a glycogen storage hypertrophy and a shortened PQ interval as opposed to what has been observed in humans carrying the N485I mutation (38).…”

AMP-Activated Protein Kinase α1 Regulates Cardiac Gap Junction Protein Connexin 43 and Electrical Remodeling Following Pressure Overload

“…Ampkα1 further downregulates gap junction protein beta 2 [12]. Mutations in the Ampkγ2 subunit leading to increased Ampk activity are associated with cardiac electrophysiologic abnormalities, hypertrophy and glycogen storage disease [20]. …”