Abstract 1299: Parallel Activation of Mitochondrial Oxidative Metabolism with Increased Cardiac Energy Expenditure is Not Dependent on Fatty Acid Oxidation
An abrupt increase in cardiac power activates NADH generation, MVO2 and ATP re-synthesis so fast that [ATP] and [ADP] do not change. Computer simulations predict that this response requires simultaneous activation of dehydrogenases (DH) in the mitochondria (mito) and cytosol in parallel with greater ATP hydrolysis, and an increased NADH/NAD+ ratio to drive ETC flux. We tested the hypothesis that 1) an abrupt transition from low to high workload increases NADH/NAD+ in the cytosol and mito, and 2) this response is so robust it does not require an increase in fatty acid oxidation (FAO). Pigs were subjected sham treatment, or 5 mins of dobutamine+aortic constriction (n=8/group). There was a ~3-fold increase in MVO2, LV power, and FAO, no change in [ATP] or [ADP], but a 50% depletion of [glycogen] and activation of the mito enzyme pyruvate DH (26±5% to 69±9% activation), and a 50% increase in tissue NADH/NAD+. Computer simulations with parallel activation of glycolysis and mito dehydrogenases predicted a similar response, with an increase in NADH/NAD+ in both mito and cytosolic compartments. The effects of mito NADH generation from FAO was addressed in a third group receiving oxfenicine, which inhibited FAO by 75% during increased work. This triggered greater glucose and lactate uptake, but did not affect tissue [ATP], [ADP] or NADH/NAD+ in vivo, while computer simulations predicted minimal effect on mito NADH/NAD+ but an increased cytosolic ratio. In conclusion, this study provides strong evidence that 1) rapid parallel activation of substrate oxidation increases the NADH/NAD+ ratio in the transition to a high workload, and 2) this robust response is not dependent upon activation of FAO.