Abstract 3723: Real Time, in vivo Observation of Oxidative Carbohydrate Metabolism Reveals the Key Regulatory Role of Acetyl-Carnitine as a Substrate Buffer in the Heart
Mismatches between glycolysis, pyruvate dehydrogenase (PDH) flux and oxidative Krebs cycle metabolism often cause impaired cardiac energetics. We recently demonstrated the ability of hyperpolarised (HP) [2–13C]pyruvate to simultaneously monitor PDH and Krebs cycle flux ex vivo, by using magnetic resonance spectroscopy (MRS) to follow the real time conversions of HP [2–13C]pyruvate into citrate, glutamate and acetylcarnitine. The aim of this study was to use HP [2–13C]pyruvate in vivo to monitor the integration of cardiac PDH and Krebs cycle fluxes, focusing on the role of acetylcarnitine in balancing cardiac substrate supply and utilization. Three groups of rats (n=6) were examined: controls, a dobutamine-infused group with elevated cardiac workload and a dichloroacetate (DCA)-infused group with maximal PDH flux. HP [2–13C]pyruvate was infused into the rats in an MR scanner and cardiac spectra were acquired every second. Conversions of pyruvate to citrate, glutamate and acetylcarnitine were monitored and compared amongst groups. Observed citrate and glutamate production was identical amongst all experimental groups, indicating that neither energy demand nor PDH flux shifted the relative contribution of pyruvate-derived acetyl CoA to the Krebs cycle. However, compared with controls, dobutamine decreased the observed acetylcarnitine by 32% whereas DCA increased acetylcarnitine production by 52%. These results suggest that acetylcarnitine buffered variations in the supply and demand of pyruvate-derived acetyl units to the Krebs cycle. Therefore acetylcarnitine may represent a promising therapeutic target in balancing pathological metabolism.