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 γ2-subunit of AMPK cause cardiac hypertrophy associated with Wolff-Parkinson-White syndrome, characterized by ventricular preexcitation. 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 γ2 harboring a mutation of arginine residue 531 to glycine (RG-TG) develop a striking cardiac phenotype by 4 wk 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 after phosphorylation by an upstream AMPK kinase. At 1 wk of age, there was no detectable evidence of a cardiac phenotype, and AMPK activity in RG-TG hearts was similar to that in nontransgenic, control mice. We propose that mutations in γ2 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.
Functional Analysis of Mutations in the γ2Subunit of AMP-activated Protein Kinase Associated with Cardiac Hypertrophy and Wolff-Parkinson-White Syndrome
