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Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-¹³C]pyruvate.

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.

SUBMITTER: Park JM

PROVIDER: S-EPMC3726546 | biostudies-other | 2013 Oct

REPOSITORIES: biostudies-other

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Project description:IntroductionThe normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility.MethodsGood Manufacturing Practice [2-13C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner.ResultsThe study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13C]lactate, TCA-associated metabolite [5-13C]glutamate, and [1-13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C-labeling of lactate, glutamate, and acetylcarnitine from 13C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation).ConclusionsHP [2-13C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Project description:Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer's disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6?months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p?<?0.01) and increased conversion from pyruvate to lactate (p?<?0.001) in the brain. The hippocampus and striatum showed the highest conversion ratio. The functional integrity of the blood-brain barrier tested by dynamic contrast-enhanced MR imaging showed no difference to the control. Lactate was increased in the cortex (p?<?0.01) and striatum (p?<?0.05), while PDH activity was decreased in the cortex (p?<?0.01) and striatum (p?<?0.001) and the phosphorylated PDH was increased in the striatum (p?<?0.05). Mice fed HFD showed less efficiency in learning memory compared with control (p?<?0.05). To determine whether hyperpolarized 13C-pyruvate magnetic resonance (MR) spectroscopy could detect a much earier event in the brain. Mice fed HFD for 3?months did not show a detectable cognitive decline in water maze based learning memory. Hyperpolarized [1-13C] pyruvate MR spectroscopy showed increased lactate conversion (P?<?.001), but no difference in cerebral perfusion. These results suggest that the increased hyperpolarized [1-13C] lactate signal in the brain of HFD-fed mice represent that altered metabolic alteration toward to glycolysis and hypoperfusion by the long-term metabolic stress by HFD further promote to glycolysis. The hyperpolarized [1-13C] pyruvate MR spectroscopy can be used to monitor the brain metabolism and will provide information helpful to understand the disease process.

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Measuring mitochondrial metabolism in rat brain in vivo using MR Spectroscopy of hyperpolarized [2-¹³C]pyruvate.

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