A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia |
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Authors: | Banerjee Sanjay K Ramani Ravi Saba Samir Rager Jennifer Tian Rong Mathier Michael A Ahmad Ferhaan |
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Affiliation: | Cardiovascular Institute, Department of Medicine, University of Pittsburgh, S558, Pittsburgh, PA 15213, USA. |
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Abstract: | Dominant mutations in the gamma2 regulatory subunit of AMP-activated protein kinase (AMPK), encoded by the gene PRKAG2, cause glycogen storage cardiomyopathy. We sought to elucidate the effect of the Thr400Asn (T400N) human mutation in a transgenic mouse (TGT400N) on AMPK activity, and its ability to protect the heart against ischemia-reperfusion injury. TGT400N hearts had markedly vacuolated myocytes, excessive accumulation of glycogen, hypertrophy, and preexcitation. Early activation of myocardial AMPK, followed by depression, and then recovery to wild-type levels was observed. AMPK activity correlated inversely with glycogen content. Partial rescue of the phenotype was observed when TGT400N mice were crossbred with TGalpha2DN mice, which overexpress a dominant negative mutant of the AMPK alpha2 catalytic subunit. TGT400N hearts had greater infarct sizes and apoptosis when subjected to ischemia-reperfusion. Increased AMPK activity is responsible for glycogen storage cardiomyopathy. Despite high glycogen content, the TGT400N heart is not protected against ischemia-reperfusion injury. |
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Keywords: | Glycogen cardiomyopathy AMPK Transgenic mouse model Cardiac hypertrophy Myocardial ischemia-reperfusion |
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