Increased adenosine monophosphate-activated protein kinase activity in rathearts with pressure-overload hypertrophy

Background-Recent reports suggest that activation of adenosine monophosphat e (AMP)-activated protein kinase (AMPK), in response to acute changes in ce llular energy status in cardiac and skeletal muscles, results in altered su bstrate utilization. We hypothesized that chronic alterations in myocardial energetics in hypertrophied hearts (left ventricular hypertrophy, LVH) wil l lead to elevated AMPK activity, which in turn regulates substrate utiliza tion. Methods and Results-Using P-31 NMR spectroscopy and biochemical assays, we found that in LVH hearts, adenosine triphosphate (ATP) concentration decrea sed by 10%, phosphocreatine concentration decreased by 30%, and total creat ine concentration was unchanged. Thus, the ratio of phosphocreatine/creatin e decreased to one third of controls, and the ratio of AMP/ATP increased to 5 times above controls. These changes were associated with increased alpha (1) and alpha (2) AMPK activity (3.5- and 4.8-fold above controls, respect ively). The increase in AMPK a, activity was accompanied by a 2-fold increa se in alpha (1) expression, whereas a2 expression was decreased by 30% in L VH. The basal rate of 2-deoxyglucose uptake increased by 3-fold in LVH, whi ch was associated with an increased amount of glucose transporters present on the plasma membrane. Conclusions-These results demonstrate for the first time that chronic chang es in myocardial energetics in hypertrophied hearts are accompanied by sign ificant elevations in AMPK activity and isoform-specific alterations in AMP K expression. It also raises the possibility that AMPK signaling plays an i mportant role in regulating substrate utilization in hypertrophied hearts.