Modeling the glycolytic pathway in human skeletal muscle tissue; understanding the regulation of its hundredfold dynamic range

Objective:During vigorous exercise, glycolytic flux in human skeletal muscle tissue increases more than hundredfold. Although the glycolytic pathway in general has been the subject of many experimental and computational studies, it is still largely unknown how this large dynamic range of skeletal muscle glycolysis is achieved and controlled. The hypothesis was tested that the bottleneck is not our understanding of the high flux regime, but instead in homeostasis of rest metabolism. We augmented the computational model of glycolysis of Lambeth and Kushmerick (Ann Biomed Eng. 2002, 30(6): 808-827). Model simulations were validated with in vivo 31P NMR measurements.Results:The existing model with mammalian kinetic parameters was re-parameterized for human skeletal muscle by estimating Vmax parameters based upon in vivo measurements of maximal glycolytic fluxes. Noninvasive, in vivo measurements of muscle energetics were obtained with 31P NMR spectroscopy. 31P NMR spectra were recorded during high intensity, in-magnet bicycle exercise performed until exhaustion and dynamics of [PCr], [ATP], [Pi], [Glucose-1P], [Glucose-6P] and [Fructose-6P] were obtained. Both the original and the re-parameterized model predicted an unphysiologically high resting flux. Including an additional suppressing regulatory mechanism yielded a model able to reproduce the 31P NMR data.Conclusion:The re-parameterized, augmented model was able to reproduce the hundredfold dynamic range of glycolytic flux in human skeletal muscle tissue; model simulations agreed very well with in vivo measurements of muscle metabolism. We speculate that detachment of enzymes from the cytoskeleton could be an important mechanism in the regulation of the glycolytic resting rate.