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Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected ¹³C NMR spectroscopy.

ABSTRACT: Determination of oxidative metabolism in the brain using in vivo ¹³C NMR spectroscopy (¹³C MRS) typically requires repeated blood sampling throughout the study to measure blood glucose concentration and fractional enrichment (input function). However, drawing blood from small animals, such as young rats, placed deep inside the magnet is technically difficult due to their small total blood volume. In the present study, a custom-built animal holder enabled temporary removal of the animal from the magnet for blood collection, followed by accurate repositioning in the exact presampling position without degradation of B? shimming. ¹³C label incorporation into glutamate C4 and C3 positions during a 120 min [1,6-¹³C?] glucose infusion was determined in 28-day-old rats (n = 4) under ?-chloralose sedation using localized, direct-detected in vivo ¹³C MRS at 9.4T. The tricarboxylic acid cycle activity rate (V(TCA)) determined using a one-compartment metabolic modeling was 0.67 ± 0.13 ?mol/g/min, a value comparable to previous ex vivo studies. This methodology opens the avenue for in vivo measurements of brain metabolic rates using ¹³C MRS in small animals.

SUBMITTER: Ennis K

PROVIDER: S-EPMC3184325 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected ¹³C NMR spectroscopy.

Ennis Kathleen K Deelchand Dinesh Kumar DK Tkac Ivan I Henry Pierre-Gilles PG Rao Raghavendra R

Neurochemical research 20110610 11

Determination of oxidative metabolism in the brain using in vivo ¹³C NMR spectroscopy (¹³C MRS) typically requires repeated blood sampling throughout the study to measure blood glucose concentration and fractional enrichment (input function). However, drawing blood from small animals, such as young rats, placed deep inside the magnet is technically difficult due to their small total blood volume. In the present study, a custom-built animal holder enabled temporary removal of the animal from the ...[more]

PMID: 21660589

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Project description:ObjectivesGlioblastoma multiforme (GBM), the most aggressive glial brain tumors, can metabolize glucose through glycolysis and mitochondrial oxidation pathways. While specific dependencies on those pathways are increasingly associated with treatment response, detecting such GBM subtypes in vivo remains elusive. Here, we develop a dynamic glucose-enhanced deuterium spectroscopy (DGE 2H-MRS) approach for differentially assessing glucose turnover rates through glycolysis and mitochondrial oxidation in mouse GBM and explore their association with histologic features of the tumor and its microenvironment.Materials and methodsGL261 and CT2A glioma allografts were induced in immunocompetent mice and scanned in vivo at 9.4 Tesla, harnessing DGE 2H-MRS with volume selection and Marchenko-Pastur PCA (MP-PCA) denoising to achieve high temporal resolution. Each tumor was also classified by histopathologic analysis and assessed for cell proliferation (Ki67 immunostaining), while the respective cell lines underwent in situ extracellular flux analysis to assess mitochondrial function.ResultsMP-PCA denoising of in vivo DGE 2H-MRS data significantly improved the time-course detection (~2-fold increased Signal-to-Noise Ratio) and fitting precision (-19 ± 1 % Cramér-Rao Lower Bounds) of 2H-labelled glucose, and glucose-derived glutamate-glutamine (Glx) and lactate pools in GL261 and CT2A orthotopic tumors. Kinetic modeling further indicated inter-tumor heterogeneity of glucose consumption rate for glycolysis and oxidation during a defined epoch of active proliferation in both cohorts (19 ± 1 days post-induction), with consistent volumes (38.3 ± 3.4 mm3) and perfusion properties prior to marked necrosis. Histopathologic analysis of these tumors revealed clear differences in tumor heterogeneity between the two GBM models, aligned with metabolic differences of the respective cell lines monitored in situ. Importantly, glucose oxidation (i.e. Glx synthesis and elimination rates: 0.40 ± 0.08 and 0.12 ± 0.03 mM min-1, respectively) strongly correlated with cell proliferation across the pooled cohorts (R = 0.82, p = 0.001; and R = 0.80, p = 0.002, respectively), regardless of tumor morphologic features or in situ metabolic characteristics of each GBM model.ConclusionsOur fast DGE 2H-MRS enables the quantification of glucose consumption rates through glycolysis and mitochondrial oxidation in mouse GBM, which is relevant for assessing their modulation in vivo according to tumor microenvironment features such as cell proliferation. This novel application augurs well for non-invasive metabolic characterization of glioma or other cancers with mitochondrial oxidation dependencies.

Dataset Information

Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected ¹³C NMR spectroscopy.

Publications

Determination of oxidative glucose metabolism in vivo in the young rat brain using localized direct-detected ¹³C NMR spectroscopy.

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