Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance
Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance
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DOI：
10.1016/j.yjmcc.2015.08.012
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发表时间：
2015-10-01
影响因子：
5
通讯作者：
Comment, Arnaud
中科院分区：
文献类型：
--
作者：
Bastiaansen, Jessica A. M.;Cheng, Tian;Comment, Arnaud
背景：心脏依赖于持续的能量产生，其中的不平衡直接损害心脏功能。三羧酸（TCA）循环是健康心肌中能量产生的主要手段，但由于大多数代谢物的浓度低，直接无创定量代谢通量具有挑战性。超极化C-13磁共振波谱（MRS）提供了在体内真实的时间测量细胞代谢的机会。这项工作的目的是非侵入性地测量心肌TCA循环流量（V-TcA）在体内在一个单一minut.Methods和结果：超极化[1-C-13]醋酸酯在不同浓度的健康大鼠。C-13掺入到[1-C-13]乙酰肉毒碱和TCA循环中间体[5-C-13]柠檬酸盐中的时间分辨率为3 s。不同的动力学模型建立和评估，以确定代谢通量，同时拟合乙酸，乙酰卡米汀，柠檬酸盐的C-13标记的演变。V-TCA估计为6.7 +/- 1.7 μ mol。g（-1）。min（-1）（干重），并且最好用仅使用柠檬酸盐和乙酰肉毒碱中的标记的模型估计，独立于前体。TCA循环速率与柠檬酸盐/乙酸盐代谢物比值不呈线性关系，因此无法使用比率法进行定量。柠檬酸盐的C-13信号演变，即柠檬酸盐形成与注射的乙酸盐的量无关，而乙酰卡米丁的C-13信号演变显示与注射的乙酸盐的剂量依赖性。柠檬酸盐的C-13标记没有相关的乙酰肉碱，导致的假设，乙酰肉碱的形成是不是一个指标的线粒体TCA循环活动在heart.Conclusions：超极化[1-C-13]乙酸是一个代谢探针的丙酮酸脱氢酶（PDH）活性独立。它允许直接估计V-TCA在体内，这被证明是既不依赖于所施用的醋酸剂量，也不依赖于C-13标记的乙酰肉毒碱。动态C-13 MRS结合注射超极化[1-C-13]醋酸盐可以测量心脏功能受损期间的代谢变化。(C)2015爱思唯尔有限公司版权所有。
Background: The heart relies on continuous energy production and imbalances herein impair cardiac function directly. The tricarboxylic acid (TCA) cycle is the primary means of energy generation in the healthy myocardium, but direct noninvasive quantification of metabolic fluxes is challenging due to the low concentration of most metabolites. Hyperpolarized C-13 magnetic resonance spectroscopy (MRS) provides the opportunity to measure cellular metabolism in real time in vivo. The aim of this work was to noninvasively measure myocardial TCA cycle flux (V-TcA) in vivo within a single minute.Methods and results: Hyperpolarized [1-C-13]acetate was administered at different concentrations in healthy rats. C-13 incorporation into [1-C-13]acetylcarnitine and the TCA cycle intermediate [5-C-13]citrate was dynamically detected in vivo with a time resolution of 3 s. Different kinetic models were established and evaluated to determine the metabolic fluxes by simultaneously fitting the evolution of the C-13 labeling in acetate, acetylcamitine, and citrate. V-TCA was estimated to be 6.7 +/- 1.7 mu mol . g(-1) . min(-1) (dry weight), and was best estimated with a model using only the labeling in citrate and acetylcarnitine, independent of the precursor. The TCA cycle rate was not linear with the citrate-to-acetate metabolite ratio, and could thus not be quantified using a ratiometric approach. The C-13 signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the C-13 signal evolution of acetylcamitine revealed a dose dependency with the injected acetate. The C-13 labeling of citrate did not correlate to that of acetylcarnitine, leading to the hypothesis that acetylcarnitine formation is not an indication of mitochondrial TCA cycle activity in the heart.Conclusions: Hyperpolarized [1-C-13]acetate is a metabolic probe independent of pyruvate dehydrogenase (PDH) activity. It allows the direct estimation of V-TCA in vivo, which was shown to be neither dependent on the administered acetate dose nor on the C-13 labeling of acetylcarnitine. Dynamic C-13 MRS coupled to the injection of hyperpolarized [1-C-13]acetate can enable the measurement of metabolic changes during impaired heart function. (C) 2015 Elsevier Ltd. All rights reserved.