Anesthesiology & Pain Medicine >> Research >> Focus Areas >> Mitochondrial Biology & Genomics >> The Role of Gamma 2 AMPK in the Heart
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Research Focus Areas:
Mitochondrial Biology & Genomics

The Role of Gamma 2 AMPK in the Heart

Principal Investigators

M. Kim, Ph.D., R. Tian, M.D., Ph.D.

Description

AMP-activated protein kinase (AMPK) is a key regulator in energy homeostasis within the cell, hence a promising drug target for obesity and metabolic syndrome. AMPK is a heterotrimeric complex composed of catalytic alpha-subunit and regulatory beta- and gamma-subunits with multiple isoforms for each subunit. Many studies have shown that AMPK is activated during cardiac stress, and failure to increase AMPK activity is associated with poor stress responses in the heart of mouse models. However, it is not still clear about the role of AMPK in the intact heart. Recently, point mutations in the regulatory gamma 2-subunit (encoded by PRKAG2 gene) have been shown to cause glycogen storage cardiomyopathy in humans and PRKAG2 cardiomyopathy is faithfully recapitulated in transgenic mice overexpressing mutant PRKAG2 N488I in the heart. The disease-causing mutation (N488I) caused aberrant activation of AMPK in the absence of energetic deficit, and the cardiomyopathy phenotype could be rescued by inhibition of AMPK activity. However, the underlying mechanisms by which PRKAG2 N488I point mutation causes excessive glycogen storage and cardiac hypertrophy have not been well defined. In order to further understand the role of PRKAG2 in the heart, we propose two specific aims: Specific Aim 1: To study cardiac hypertrophy associated aberrant AMPK activity without excessive glycogen accumulation in the PRKAG2 N488I mutant hearts. Specific Aim 2: To investigate cardiac hypertrophy associated with ablation of PRKAG2 gene in the normal and/or stressed hearts. Successful performance of the specific aims will provide important insights into the understanding of the AMPK function in the intact heart, and will ultimately benefit the pharmacological targeting of AMPK.

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