On the reliability of 13C metabolic modeling with two-compartment neuronal-glial models

Metabolic modeling of C-13 NMR spectroscopy (C-13 MRS) data using two-compartment neuronal-glial models enabled non-invasive measurements of the glutamate-glutamine cycle rate (V-NT) in the brain in vivo. However, the reliability of such two-compartment metabolic modeling has not been examined thoroughly. This study uses Monte-Carlo simulations to investigate the reliability of metabolic modeling of C-13 positional enrichment time courses measured in brain amino acids such as glutamate and glutamine during [1- C-13]- or [1,6- C-13(2)]glucose infusion. Results show that the determination Of VNT is not very precise under experimental conditions typical of in vivo NMR studies, whereas the neuronal TCA cycle rate V-TCA(N) is determined with a much higher precision. Consistent with these results, simulated C-13 positional enrichment curves for glutamate and glutamine are much more sensitive to the value Of V-TCA(N) than to the value of V-NT. We conclude that the determination of the glutamate-glutamine cycle rate V-NT using C-13 MRS is relatively unreliable when fitting C-13 positional enrichment curves obtained during [1- C-13] or [1,6- C-13(2)]glucose infusion. Further developments are needed to improve the determination Of V-NT, for example using additional information from C-13-C-13 isotoporners and/or using glial specific substrates such as [2- C-13]acetate. (c) 2007 Wiley-Liss, Inc.