(568c) Elucidating Brain Metabolism by Dynamic 13C Isotopomer Analysis

Metabolic modeling of 13C turnover curves obtained during infusion of a 13C labeled substrate with a two-compartment neuronal-glial model allows measurement of compartmentalized metabolic fluxes such as the neuronal and glial TCA cycle rates and the rate of glutamate-glutamine cycle. Recently, we reported in vivo measurements of time courses for multiple 13C-13C isotopomers, which appear as multiplets in 13C NMR spectra [1]. The goal of the present work was to extend the isotopomer neuronal-glial metabolic model [2,3] in order to simultaneously fit multiple 13C isotopomer curves of glutamate, glutamine and aspartate. The extended metabolic network includes well-established neuronal vesicular and cytosolic glutamate, separated brain pyruvate and lactate pools, glial and neuronal anaplerosis at the level of succinyl-CoA, reversible fluxes between TCA cycle intermediates OAA and succinate. When additional information (such as fluxes and metabolic pools) based on the brain metabolic network were included, the fits for each isotopomer curve was good. The resulting fitted metabolic fluxes (in μmol/g/min) were: VTCA(n)= 0.94 , VTCA(g)= 0.41, VPC= 0.08, VX=23 and VNT= 0.09 and these were in agreement with rates reported in previous studies [3]. In addition, the concentration of the vesicular neuronal glutamate was estimated at 1.5 μmol/g. References [1] Henry NMR Biomed 16, 400, 2003; [2] Shestov ISMRM 2007; [3] Gruetter AJP 281, E100, 2001 This work was supported by NIH grants R01NS38672 and P41RR08079