Mutation in the γ2-Subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage

Maengjo Kim, Roger W. Hunter, Lorena Garcia-Menendez, Guohua Gong, Yu-Ying Yang, Stephen C. Kolwicz, Jason Xu, Kei Sakamoto, Wang Wang, Rong Tian

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    44 Citations (Scopus)

    Abstract

    Rationale: AMP-activated protein kinase is a master regulator of cell metabolism and an attractive drug target for cancer and metabolic and cardiovascular diseases. Point mutations in the regulatory ?2-subunit of AMP-activated protein kinase (encoded by Prkag2 gene) caused a unique form of human cardiomyopathy characterized by cardiac hypertrophy, ventricular preexcitation, and glycogen storage. Understanding the disease mechanisms of Prkag2 cardiomyopathy is not only beneficial for the patients but also critical to the use of AMP-activated protein kinase 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 gene (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 preexcitation but did not affect the excessive cardiac growth in R2M mice. The progrowth effect in R2M hearts was mediated via increased insulin sensitivity and hyperactivity of Akt, resulting in activation of mammalian target of rapamycin and inactivation of forkhead box O transcription factor-signaling pathways. Consequently, cardiac myocyte proliferation during the postnatal period was enhanced in R2M hearts followed by hypertrophic growth in adult hearts. Inhibition of mammalian target of rapamycin activity by rapamycin or restoration of forkhead box O transcription factor activity by overexpressing forkhead box O transcription factor 1 rescued the abnormal cardiac growth.

    Conclusions: Our study reveals a novel mechanism for Prkag2 cardiomyopathy, independent of glycogen storage. The role of ?2-AMP-activated protein kinase in cell growth also has broad implications in cardiac development, growth, and regeneration.

    Original languageEnglish
    Pages (from-to)966-975
    Number of pages10
    JournalCirculation Research
    Volume114
    Issue number6
    Early online date6 Feb 2014
    DOIs
    Publication statusPublished - 14 Mar 2014

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  • Cite this

    Kim, M., Hunter, R. W., Garcia-Menendez, L., Gong, G., Yang, Y-Y., Kolwicz, S. C., Xu, J., Sakamoto, K., Wang, W., & Tian, R. (2014). Mutation in the γ2-Subunit of AMP-activated protein kinase stimulates cardiomyocyte proliferation and hypertrophy independent of glycogen storage. Circulation Research, 114(6), 966-975. https://doi.org/10.1161/CIRCRESAHA.114.302364