| Abstrakt: |
Previous studies have demonstrated that using hyperpolarized [2-13C]pyruvate as a contrast agent can reveal 13C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle-mediated oxidation of [2-13C]pyruvate are the result of several metabolic steps. In the instance of the [5-13C]glutamate signal, the amplitude can be modulated by changes to the rates of pyruvate dehydrogenase (PDH) flux, TCA cycle flux and metabolite pool size. Also key is the malate-aspartate shuttle, which facilitates the transport of cytosolic reducing equivalents into the mitochondria for oxidation via the malate--α-ketoglutarate transporter, a process coupled to the exchange of cytosolic malate for mitochondrial α-ketoglutarate. In this study, we investigated the mechanism driving the observed changes to hyperpolarized [2-13C]pyruvate metabolism. Using hyperpolarized [1,2-13C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13C--glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non-invasively. Via the [1-13C]pyruvate label, we observed more than a five-fold increase in the cytosolic conversion of pyruvate to [1-13C]lactate and [1-13C]alanine with higher workload. 13C--Bicarbonate production by PDH was increased by a factor of 2.2. Cardiac cine imaging measured a two-fold increase in cardiac output, which is known to couple to TCA cycle turnover. Via the [2-13C]pyruvate label, we observed that 13C--acetylcarnitine production increased 2.5-fold in proportion to the 13C--bicarbonate signal, whereas the 13C--glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13C--glutamate signal relative to the amount of 13C--labeled acetyl-coenzyme A (acetyl-CoA) entering the TCA cycle was decreased by 40%. The data strongly suggest that NADH (reduced form of nicotinamide adenine dinucleotide) shuttling from the cytosol to the mitochondria via the malate--aspartate shuttle is limited on adrenergic activation. Changes in [5-13C]glutamate production from [2-vC]pyruvate may play an important future role in non-invasive myocardial assessment in patients with cardiovascular diseases, but careful interpretation of the results is required. [ABSTRACT FROM AUTHOR] |
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