Measuring mitochondrial metabolism in rat brain <i>in vivo</i> using MR Spectroscopy of hyperpolarized [2‐¹³C]pyruvate

TLDR

Hyperpolarized [1‑13C]pyruvate has been used to probe metabolism, while [2‑13C]pyruvate, which preserves the labeled carbon for acetyl‑CoA, has been applied to cardiac mitochondrial studies but has rarely been used in brain, where only lactate labeling has been reported. The authors performed single‑time‑point chemical‑shift imaging of hyperpolarized [2‑13C]pyruvate in rat brain and, to stimulate flux to acetyl‑CoA, infused dichloroacetate during the experiment. They detected [5‑13C]glutamate, [1‑13C]acetylcarnitine, and [1‑13C]citrate in addition to the expected [2‑13C]pyruvate and lactate, and dichloroacetate produced a 40 % rise in brain [5‑13C]glutamate and a trend toward higher citrate, demonstrating that [2‑13C]pyruvate can image brain mitochondrial and TCA cycle activity. © 2013 John Wiley & Sons, Ltd.

Abstract

Hyperpolarized [1‐ 13 C]pyruvate ([1‐ 13 C]Pyr) has been used to assess metabolism in healthy and diseased states, focusing on the downstream labeling of lactate (Lac), bicarbonate and alanine. Although hyperpolarized [2‐ 13 C]Pyr, which retains the labeled carbon when Pyr is converted to acetyl‐coenzyme A, has been used successfully to assess mitochondrial metabolism in the heart, the application of [2‐ 13 C]Pyr in the study of brain metabolism has been limited to date, with Lac being the only downstream metabolic product reported previously. In this study, single‐time‐point chemical shift imaging data were acquired from rat brain in vivo . [5‐ 13 C]Glutamate, [1‐ 13 C]acetylcarnitine and [1‐ 13 C]citrate were detected in addition to resonances from [2‐ 13 C]Pyr and [2‐ 13 C]Lac. Brain metabolism was further investigated by infusing dichloroacetate, which upregulates Pyr flux to acetyl‐coenzyme A. After dichloroacetate administration, a 40% increase in [5‐ 13 C]glutamate from 0.014 ± 0.004 to 0.020 ± 0.006 ( p = 0.02), primarily from brain, and a trend to higher citrate (0.002 ± 0.001 to 0.004 ± 0.002) were detected, whereas [1‐ 13 C]acetylcarnitine was increased in peripheral tissues. This study demonstrates, for the first time, that hyperpolarized [2‐ 13 C]Pyr can be used for the in vivo investigation of mitochondrial function and tricarboxylic acid cycle metabolism in brain. Copyright © 2013 John Wiley &amp; Sons, Ltd.