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

R Tian, N Musi, J D'Agostino, M F Hirshman, L J Goodyear
Circulation 2001 October 2, 104 (14): 1664-9

BACKGROUND: Recent reports suggest that activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), in response to acute changes in cellular energy status in cardiac and skeletal muscles, results in altered substrate utilization. We hypothesized that chronic alterations in myocardial energetics in hypertrophied hearts (left ventricular hypertrophy, LVH) will lead to elevated AMPK activity, which in turn regulates substrate utilization.

METHODS AND RESULTS: Using (31)P NMR spectroscopy and biochemical assays, we found that in LVH hearts, adenosine triphosphate (ATP) concentration decreased by 10%, phosphocreatine concentration decreased by 30%, and total creatine concentration was unchanged. Thus, the ratio of phosphocreatine/creatine 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, respectively). The increase in AMPK alpha(1) activity was accompanied by a 2-fold increase in alpha(1) expression, whereas alpha(2) expression was decreased by 30% in LVH. The basal rate of 2-deoxyglucose uptake increased by 3-fold in LVH, which was associated with an increased amount of glucose transporters present on the plasma membrane.

CONCLUSIONS: These results demonstrate for the first time that chronic changes in myocardial energetics in hypertrophied hearts are accompanied by significant elevations in AMPK activity and isoform-specific alterations in AMPK expression. It also raises the possibility that AMPK signaling plays an important role in regulating substrate utilization in hypertrophied hearts.

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