Real‐time assessment of Krebs cycle metabolism using hyperpolarized C magnetic resonance spectroscopy

Schroeder, Marie A.; Atherton, Helen; Ball, Daniel R.; Cole, Mark A.; Heather, Lisa C.; Griffin, Julian L.; Clarke, Kieran; Radda, George K.; Tyler, Damian J.

doi:10.1096/fj.09-129171

Cited by 199 publications

(242 citation statements)

References 37 publications

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“…The delayed observation of citrate with respect to acetylcarnitine is consistent with the role of carnitine as a shuttle for acetyl groups across the mitochondrial membrane, and as a mitochondrial buffer for excess acetylCoA. A similar evolution of the 13 C labeling of citrate was detected using the hyperpolarized carbohydrate [2-13 C]pyruvate [55]. However, in these studies the mitochondrial uptake of pyruvate is mediated by PDH where acetylcarnitine acts as a buffer for excess acetylCoA, which was shown to be a rapid exchange process [56].…”

Section: Discussionsupporting

confidence: 70%

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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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 13 C 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 [1-13 C]acetate was administered at different concentrations in healthy rats. 13C incorporation into [1-13 C]acetylcarnitine and the TCA cycle intermediate [5-13 C]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 13 C labeling in acetate, acetylcarnitine, and citrate. V TCA was estimated to be 6.7 ± 1.7 μmol · 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 13 C signal evolution of citrate, i.e. citrate formation was independent of the amount of injected acetate, while the 13 C signal evolution of acetylcarnitine revealed a dose dependency with the injected acetate. The 13 C 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 [1-13 C]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 13 C labeling of acetylcarnitine. Dynamic 13 C MRS coupled to the injection of hyperpolarized [1-13 C]acetate can enable the measurement of metabolic changes during impaired heart function.

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Section: Discussionsupporting

confidence: 70%

Direct noninvasive estimation of myocardial tricarboxylic acid cycle flux in vivo using hyperpolarized 13C magnetic resonance

Bastiaansen

Tian

Lei

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…This agrees with our recent observation in the hypertrophied heart, in which a larger 13 C-citrate signal (from increased pyruvate anaplerosis) was recorded. 28 Moreover, detection of citrate pool with hyperpolarized [2-13 C]pyruvate substrate has recently been demonstrated to be feasible in the study of myocardial TCA flux 29 ; therefore, similar measurements in the insulin-resistant liver will undoubtedly aid in validating the hypothesis that an enlarged citrate pool supports FAS. Metformin is used clinically to counter elevated FAS and gluconeogenesis in diabetes, primarily through its activation of adenosine-monophosphateactivated protein kinase.…”

Section: Discussionmentioning

confidence: 99%

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

et al. 2013

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The pathogenesis of type 2 diabetes is characterized by impaired insulin action and increased hepatic glucose production (HGP). Despite the importance of hepatic metabolic aberrations in diabetes development, there is currently no molecular probe that allows measurement of hepatic gluconeogenic pathways in vivo and in a noninvasive manner. In this study, we used hyperpolarized carbon 13 ( 13 C)-labeled pyruvate magnetic resonance spectroscopy (MRS) to determine changes in hepatic gluconeogenesis in a high-fat diet (HFD)-induced mouse model of type 2 diabetes. Compared with mice on chow diet, HFD-fed mice displayed higher levels of oxaloacetate, aspartate, and malate, along with increased 13 C label exchange rates between hyperpolarized [1-13 C]pyruvate and its downstream metabolites, [1-13 C]malate and [1-13 C]aspartate. Biochemical assays using liver extract revealed up-regulated malate dehydrogenase activity, but not aspartate transaminase activity, in HFD-fed mice. Moreover, the 13 C label exchange rate between [1-13 C]pyruvate and [1-13 C]aspartate (k pyr->asp ) exhibited apparent correlation with gluconeogenic pyruvate carboxylase (PC) activity in hepatocytes. Finally, up-regulated HGP by glucagon stimulation was detected by an increase in aspartate signal and k pyr->asp , whereas HFD mice treated with metformin for 2 weeks displayed lower production of aspartate and malate, as well as reduced k pyr->asp and 13 C-label exchange rate between pyruvate and malate, consistent with down-regulated gluconeogenesis. Conclusion: Taken together, we demonstrate that increased PC flux is an important pathway responsible for increased HGP in diabetes development, and that pharmacologically induced metabolic changes specific to the liver can be detected in vivo with a hyperpolarized 13 C-biomolecular probe. Hyperpolarized 13 C MRS and the determination of metabolite exchange rates may allow longitudinal monitoring of liver function in disease development. (HEPATOLOGY 2013;57:515-524) T he coordinated actions of insulin and glucagon ensure that glucose homeostasis is maintained across a wide range of physiological conditions. In obesity-associated type 2 diabetes, control of glucose metabolism by these two regulatory hormones is impaired, resulting in hepatic insulin resistance and excessive endogenous glucose production. 1 To date, it has not been possible to evaluate this metabolic dysfunction in the liver by a noninvasive in vivo method.Carbon-13 ( 13 C) magnetic resonance spectroscopy (MRS) has been used to study hepatic gluconeogenesis since the 1980s. However, its inherent low sensitivity has largely limited its application to the study of steady-state metabolism in perfused livers with long Abbreviations: ALT, alanine transaminase; AST, aspartate transaminase; 13 C, carbon-13; ChREBP, carbohydrate response element-binding protein; FAS, fatty acid synthase; G-6-Pase, glucose-6-phosphatase; HFD, high-fat diet; HGP, hepatic glucose production; IHTG, intrahepatic triglyceride; IPGTT, intraperitoneal glucose toleranc...

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“…Recently, hyperpolarized 13 C pyruvate has been used to characterize cardiac metabolism noninvasively in the rat (4,5) and the pig (6). In these studies, [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate was injected intravenously, and cardiac spectra were acquired with spatial localization to the heart either by coil location or by slice selection and single-step phase encoding of the field of view.…”

Section: Introductionmentioning

confidence: 99%

“…This sequence permits whole-heart coverage (6 slices, 8.8 mm in-plane resolution) in any plane, allowing imaging of the metabolites of interest, [1][2][3][4][5][6][7][8][9][10][11][12][13] C] pyruvate, [1-13 C] lactate, and 13 C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied.…”

Section: Introductionmentioning

confidence: 99%

Rapid multislice imaging of hyperpolarized ¹³C pyruvate and bicarbonate in the heart

Lau¹,

Chen²,

Ghugre³

et al. 2010

Magnetic Resonance in Med

149

247

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Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic rocesses occurring in vivo using 13 C-labeled substrates. Recently, hyperpolarized 13 C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac-gated, breath-held, whole-heart volume. In this article, the development of a rapid multislice cardiac-gated spiral 13 C imaging pulse sequence consisting of a large flip-angle spectral-spatial excitation RF pulse combined with a singleshot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.

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Real‐time assessment of Krebs cycle metabolism using hyperpolarized C magnetic resonance spectroscopy

Cited by 199 publications

References 37 publications

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

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

Rapid multislice imaging of hyperpolarized ¹³C pyruvate and bicarbonate in the heart

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Real‐time assessment of Krebs cycle metabolism using hyperpolarized C magnetic resonance spectroscopy

Cited by 199 publications

References 37 publications

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

In Vivohyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin-resistant mouse model

Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart

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Rapid multislice imaging of hyperpolarized ¹³C pyruvate and bicarbonate in the heart