Hyperpolarised [2-C]Pyruvate Uniquely Reveals the Role of Acetylcarnitine as a Mitochondrial Substrate Buffer in the Heart

Introduction In normal hearts, Krebs cycle flux is maintained by continuous citrate synthase-mediated condensation of acetyl-CoA with oxaloacetate. In turn, acetylCoA is produced from the oxidation of fatty acids, ketone bodies or glucose, via glycolysis and the enzyme pyruvate dehydrogenase (PDH). Hyperpolarised [2C]pyruvate has been used in the isolated heart to observe the relationship between PDH flux and Krebs cycle metabolism in real time, using C magnetic resonance spectroscopy (MRS) [1, 2]. Conversion of [2-C]pyruvate into the Krebs cycle related metabolites, citrate and glutamate, was observed. Further, a substantial fraction of the pyruvate oxidised by PDH was converted to acetylcarnitine [1]. Acetylcarnitine is produced by carnitine acetyltransferase (CAT), from mitochondrial acetyl-CoA and carnitine. This observation in the intact heart was consistent with that in cardiac mitochondria [3], which showed that a greater proportion of acetylcarnitine was produced from pyruvate-derived acetyl-CoA than from fatty acid-derived acetyl-CoA. These results point to clear involvement of CAT and the acetylcarnitine pool in cardiac substrate selection. However, the nature of the relationships that exists in vivo between acetylcarnitine, pyruvate oxidation, and Krebs cycle flux have yet to be determined. The aim of this study was to use hyperpolarised [2-C]pyruvate as a metabolic tracer to examine the role of acetylcarnitine in cardiac oxidative metabolism.