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Am J Physiol Heart Circ Physiol (December 9, 2005). doi:10.1152/ajpheart.01020.2005
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Submitted on September 26, 2005
Accepted on December 8, 2005

Characterisation of the role of the {gamma}2 R531G mutation in AMP-activated protein kinase in Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome

Joanna K Davies1, Dominic J Wells2, Ke Liu2, Helen R Whitrow1, Tyrone D Daniel1, Robert Grignani3, Craig A Lygate3, Jurgen E Schneider3, Gaetane Noel4, Hugh Watkins3, and David Carling1*

1 Cellular Stress Group, MRC Clinical Sciences Centre, London, United Kingdom
2 Division of Neusoscience & Mental Health, Imperial College, London, United Kingdom
3 Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
4 Laboratory of Physiological Chemistry, Christian de Duve Institute of Cellular Pathology, Brussels, Belgium

* To whom correspondence should be addressed. E-mail: dcarling{at}imperial.ac.uk.

AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a key role in the regulation of energy metabolism. In humans, mutations in the {gamma}2 subunit of AMPK cause cardiac hypertrophy associated with Wolff-Parkinson-White (WPW) syndrome, characterised by ventricular pre-excitation. The effect of these mutations on AMPK activity and in development of the disease is enigmatic. Here we report that transgenic mice with cardiac-specific expression of {gamma}2 harbouring mutation of arginine residue 531 to glycine (RG-TG) develop a striking cardiac phenotype by 4 weeks of age, including hypertrophy, impaired contractile function, electrical conduction abnormalities and marked glycogen accumulation. At this stage, AMPK activity isolated from hearts of RG-TG mice was almost completely abolished, but could be restored following phosphorylation by an upstream AMPK kinase. At 1 week of age, there was no detectable evidence of a cardiac phenotype and AMPK activity in RG-TG hearts was similar to that in non-transgenic, control mice. We propose that mutations in {gamma}2 lead to suppression of total cardiac AMPK activity secondary to increased glycogen accumulation. The subsequent decrease in AMPK activity provides a mechanism that may explain the development of cardiac hypertrophy in this model.




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