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Metabolic Modeling of Dynamic Brain 13C NMR Multiplet Data: Concepts and Simulations with a Two-Compartment Neuronal-Glial Model

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Abstract

Metabolic modeling of dynamic 13C labeling curves during infusion of 13C-labeled substrates allows quantitative measurements of metabolic rates in vivo. However metabolic modeling studies performed in the brain to date have only modeled time courses of total isotopic enrichment at individual carbon positions (positional enrichments), not taking advantage of the additional dynamic 13C isotopomer information available from fine-structure multiplets in 13C spectra. Here we introduce a new 13C metabolic modeling approach using the concept of bonded cumulative isotopomers, or bonded cumomers. The direct relationship between bonded cumomers and 13C multiplets enables fitting of the dynamic multiplet data. The potential of this new approach is demonstrated using Monte-Carlo simulations with a brain two-compartment neuronal-glial model. The precision of positional and cumomer approaches are compared for two different metabolic models (with and without glutamine dilution) and for different infusion protocols ([1,6-13C2]glucose, [1,2-13C2]acetate, and double infusion [1,6-13C2]glucose + [1,2-13C2]acetate). In all cases, the bonded cumomer approach gives better precision than the positional approach. In addition, of the three different infusion protocols considered here, the double infusion protocol combined with dynamic bonded cumomer modeling appears the most robust for precise determination of all fluxes in the model. The concepts and simulations introduced in the present study set the foundation for taking full advantage of the available dynamic 13C multiplet data in metabolic modeling.

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Abbreviations

MRS:

Magnetic resonance spectroscopy

ADM:

Atom distribution matrix

TCA cycle:

Tricarboxylic acid cycle

VNT :

Rate of glutamate-glutamine cycle

VTCA(N) :

Rate of neuronal TCA cycle

VTCA(A) :

Rate of astrocytic TCA cycle

VPC :

Rate of pyruvate carboxylase

VX :

Rate of exchange between 2-oxoglutarate and glutamate

VOUT :

Rate of lactate dilution

VDILGLN :

Rate of glutamine dilution

Glu:

Glutamate

Gln:

Glutamine

N:

Neuronal

A:

Astrocytic

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Acknowledgments

This work was supported by NIH grants P41RR008079, P41EB015894, P30NS057091 and R01NS038672 (P.G.H.).

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Authors and Affiliations

  1. Center for Magnetic Resonance Research, University of Minnesota, 2021 6th St SE, Minneapolis, MN, 55455, USA

    Alexander A. Shestov, Julien Valette, Dinesh K. Deelchand, Kâmil Uğurbil & Pierre-Gilles Henry

  2. Commissariat à l’Energie Atomique, Institut d’Imagerie Biomédicale (I²BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France

    Julien Valette

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  1. Alexander A. Shestov
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Correspondence to Pierre-Gilles Henry.

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Special Issue: In Honor of Leif Hertz.

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Shestov, A.A., Valette, J., Deelchand, D.K. et al. Metabolic Modeling of Dynamic Brain 13C NMR Multiplet Data: Concepts and Simulations with a Two-Compartment Neuronal-Glial Model. Neurochem Res 37, 2388–2401 (2012). https://doi.org/10.1007/s11064-012-0782-5

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  • DOI: https://doi.org/10.1007/s11064-012-0782-5

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