Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling
Figure 7
Ensemble predictions of metabolite concentration and flux oscillations during the cardiac cycle for selective CK isoform inhibition.
In the first row (panels A–D), the pulsatile forcing function for ATP hydrolysis is plotted. Predictions of the time courses of (E–H) relative contribution of PCr to high-energy phosphate transport, Rdiff,PCr, (I–L) ATP synthesis rate, (M–P) cytosolic ADP and (Q–T) Pi concentrations. Heart rate is 220 bpm. In the four columns we compare: no CK inhibition, 98% Mi-CK inhibition, 98% MM-CK, or both CK enzyme reactions inhibited by 98%. Black solid lines show the simulated trajectory of the optimized parameter set (Table 1). Blue shaded regions show the 95% central confidence interval for all trajectories of the ensemble of 658 parameter sets. To alter CK activity, the parameters describing maximum enzyme velocity, Vmax,Mif and Vmax,MMf, are changed to the indicated percentage. Three cardiac cycles are shown after a steady state was reached. Note that the first and the last column also appear in Figure 6 and are shown here for ease of comparison.