Modeling of Brain Metabolism and Pyruvate Compartmentation Using ¹³C NMR in Vivo: Caution Required

Abstract

Two variants of a widely used two-compartment model were prepared for fitting the time course of [1,[6][7][8][9][10][11][12][13] C 2 ]glucose metabolism in rat brain. Features common to most models were included, but in one model the enrichment of the substrates entering the glia and neuronal citric acid cycles was allowed to differ. Furthermore, the models included the capacity to analyze multiplets arising from 13 C spin-spin coupling, known to improve parameter estimates in heart. Data analyzed were from a literature report providing time courses of [1,6-13 C 2 ]glucose metabolism. Four analyses were used, two comparing the effect of different pyruvate enrichment in glia and neurons, and two for determining the effect of multiplets present in the data. When fit independently, the enrichment in glial pyruvate was less than in neurons. In the absence of multiplets, fit quality and parameter values were typical of those in the literature, whereas the multiplet curves were not modeled well. This prompted the use of robust statistical analysis (the Kolmogorov-Smirnov test of goodness of fit) to determine whether individual curves were modeled appropriately. At least 50% of the curves in each experiment were considered poorly fit. It was concluded that the model does not include all metabolic features required to analyze the data.

Metabolic Modeling of Dynamic 13C NMR Isotopomer Data in the Brain In Vivo: Fast Screening of Metabolic Models Using Automated Generation of Differential Equations

“…Nonetheless, Model 2 gave a higher lactate dilution flux in astrocytes than in neurons (Figure 5. D, grey bars), consistent with previous results by Jeffrey et al [23] and consistent with astrocytes being located closer to blood vessels than neurons.…”

“…In Model 2, separate pyruvate/lactate pools are introduced for astrocytes and neurons, with separate dilution fluxes Vdil LacA and Vdil LacN , thus allowing different fractional enrichment in neurons and astrocytes, as reported in [21], [23], [24]. This second model can be described using a total of 119 equations after simplification.…”

How to measure metabolic fluxes: a taxonomic guide for 13 C fluxomics

“…Fluxes at the organismal/tissue level Several INST studies assuming homogeneous conditions in organs and tissues have been conducted for brain metabolism, often applying in vivo 13 C NMR [44,45].…”

Triheptanoin for Glucose Transporter Type I Deficiency (G1D)

“…But glucose metabolism also fulfills other, less often-acknowledged cerebral biosynthetic requirements, which are no less-important from a clinical standpoint when they remain unmet 2 , such as anaplerosis (i.e., the replacement of the net carbon that is normally lost from the TCA pool via diffusion away from the TCA cycle). Thus, a myriad of cerebral energetic and carbon fluxes, many of which are still poorly understood quantitatively 3 , stem from brain glucose availability. This is, in turn, contingent upon the activity of the facilitative membrane glucose transporter type I (GLUT1), which permits glucose to cross the blood-brain barrier and, subsequently, transit into - and perhaps through - astrocytes.…”