Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

Abstract. Cardiac ATP-sensitive potassium (K ATP ) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress. Although under basal aerobic conditions, K ATP channels are thought to be predominately closed. Despite intense research into the roles of K ATP channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been investigated previously. Methods. Hearts from Kir6.2+/+ and Kir6.2 -/- mice were perfused in working mode and rates of glycolysis, fatty acid oxidation and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Results. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2-/- mice displayed a ~2-fold increase in fatty acid oxidation, and a 0.45-fold reduction in glycolytic rates but similar glucose oxidation rates compared with Kir6.2+/+ hearts. Kir6.2-/- hearts also possess elevated levels of activated AMPK, higher glycogen content and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2-/- hearts. Conclusions. These data indicate that K ATP channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis, prior to any metabolic insult, may contribute to the poor recovery observed in Kir6.2-/- hearts in response to exercise or ischemia-reperfusion injury. K ATP channels may therefore play an important role in the regulation of cardiac metabolism through AMPK signaling.