A PRKAG2 mutation causes biphasic changes in myocardial AMPK activity and does not protect against ischemia.

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.

• Authors: Sanjay K Banerjee, Ravi Ramani, Samir Saba, Jennifer Rager, Rong Tian, Michael A Mathier, Ferhaan Ahmad
• Journal: Biochemical and biophysical research communications (Biochem Biophys Res Commun) Vol. 360 Issue 2 Pg. 381-7 (Aug 24 2007) ISSN: 0006-291X [Print] United States
• PMID: 17597581 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• Multienzyme Complexes
• Glycogen
• PRKAA2 protein, human
• Protein Serine-Threonine Kinases
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases
• Animals
• Cardiotonic Agents
• Enzyme Activation
• Glycogen (metabolism)
• Humans
• Mice
• Mice, Transgenic
• Multienzyme Complexes (genetics, metabolism)
• Mutation
• Myocardial Reperfusion Injury (genetics, metabolism, pathology)
• Myocardium (metabolism, pathology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Structure-Activity Relationship