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Probing the cardiac malate–aspartate shuttle non‐invasively using hyperpolarized [1,2‐ 13 C 2 ]pyruvate
Author(s) -
Chen Albert P.,
Lau Angus Z.,
Gu Yiping,
Schroeder Marie A.,
Barry Jennifer,
Cunningham Charles H.
Publication year - 2018
Publication title -
nmr in biomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.278
H-Index - 114
eISSN - 1099-1492
pISSN - 0952-3480
DOI - 10.1002/nbm.3845
Subject(s) - citric acid cycle , pyruvate dehydrogenase complex , malate dehydrogenase , fumarase , cytosol , pyruvate decarboxylation , flux (metallurgy) , biochemistry , tricarboxylic acid , chemistry , metabolite , pyruvic acid , hyperpolarization (physics) , metabolism , nuclear magnetic resonance spectroscopy , enzyme , stereochemistry , organic chemistry
Previous studies have demonstrated that using hyperpolarized [2‐ 13 C]pyruvate as a contrast agent can reveal 13 C signals from metabolites associated with the tricarboxylic acid (TCA) cycle. However, the metabolites detectable from TCA cycle‐mediated oxidation of [2‐ 13 C]pyruvate are the result of several metabolic steps. In the instance of the [5‐ 13 C]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‐ 13 C]pyruvate metabolism. Using hyperpolarized [1,2‐ 13 C]pyruvate with magnetic resonance spectroscopy (MRS) in the porcine heart with different workloads, it was possible to probe 13 C–glutamate labeling relative to rates of cytosolic metabolism, PDH flux and TCA cycle turnover in a single experiment non‐invasively. Via the [1‐ 13 C]pyruvate label, we observed more than a five‐fold increase in the cytosolic conversion of pyruvate to [1‐ 13 C]lactate and [1‐ 13 C]alanine with higher workload. 13 C–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‐ 13 C]pyruvate label, we observed that 13 C–acetylcarnitine production increased 2.5‐fold in proportion to the 13 C–bicarbonate signal, whereas the 13 C–glutamate metabolic flux remained constant on adrenergic activation. Thus, the 13 C–glutamate signal relative to the amount of 13 C–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‐ 13 C]glutamate production from [2‐ 13 C]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.