The Cycling of Acetyl-Coenzyme A Through Acetylcarnitine Buffers Cardiac Substrate Supply

BACKGROUND: Carnitine acetyltransferase catalyzes the reversible conversion of acetyl-coenzyme A (CoA) into acetylcarnitine. The aim of this study was to use the metabolic tracer hyperpolarized 2-(13)Cpyruvate with magnetic resonance spectroscopy to determine whether carnitine acetyltransferase facilitates carbohydrate oxidation in the heart. METHODS AND RESULTS: Ex vivo, following hyperpolarized 2-(13)Cpyruvate infusion, the 1-(13)Cacetylcarnitine resonance was saturated with a radiofrequency pulse, and the effect of this saturation on 1-(13)Ccitrate and 5-(13)Cglutamate was observed. In vivo, 2-(13)Cpyruvate was infused into 3 groups of fed male Wistar rats: (1) controls, (2) rats in which dichloroacetate enhanced pyruvate dehydrogenase flux, and (3) rats in which dobutamine elevated cardiac workload. In the perfused heart, 1-(13)Cacetylcarnitine saturation reduced the 1-(13)Ccitrate and 5-(13)Cglutamate resonances by 63% and 51%, respectively, indicating a rapid exchange between pyruvate-derived acetyl-CoA and the acetylcarnitine pool. In vivo, dichloroacetate increased the rate of 1-(13)Cacetylcarnitine production by 35% and increased the overall acetylcarnitine pool size by 33%. Dobutamine decreased the rate of 1-(13)Cacetylcarnitine production by 37% and decreased the acetylcarnitine pool size by 40%. CONCLUSIONS: Hyperpolarized (13)C magnetic resonance spectroscopy has revealed that acetylcarnitine provides a route of disposal for excess acetyl-CoA and a means to replenish acetyl-CoA when cardiac workload is increased. Cycling of acetyl-CoA through acetylcarnitine appears key to matching instantaneous acetyl-CoA supply with metabolic demand, thereby helping to balance myocardial substrate supply and contractile function.