Multiscale and Modular Analysis of CardiacEnergy Metabolism Repairing the Broken Interfaces of Isolated SystemComponents

摘要

Computational models of large molecular systems can be assembled from modules representingbiological function emerging from interactions among a small subset of molecules. Experimen-tal information on isolated molecules can be integrated with the response of the network as awhole to estimate crucial missing parameters. As an example, a "skeleton" model is analyzed forthe module regulating dynamic adaptation of myocardial oxidative phosphorylation (OxPhos)to fluctuating cardiac energy demand. The module contains adenine nucleotides, creatine, andphosphate groups. Enzyme kinetic equations for two creatine kinase (CK) isoforms were com-bined with the response time of OxPhos (t_(mito);generalized time constant) to steps in the cardiacpacing rate to identify all module parameters. To obtaint_(mito),the time course of O_2uptake wasmeasured for the whole heart. An O_2 transport model was used to deconvolute the whole-heartresponse to the mitochondrial level. By optimizing mitochondrial outer membrane permeabilityto 21 μm/s the experimental t_(mito)= 3.7 swas reproduced. Thisin vivovalue is about four timeslarger, or smaller, respectively, than conflicting values obtained from two different in vitro stud-ies. This demonstrates an important rule for multiscale analysis: experimental responses andmodeling of the system at the larger scale allow one to estimate essential parameters for theinterfaces of components which may have been altered during physical isolation. The model cor- rectly predicts a smaller when CK activity is reduced. The model further predicts a slowerresponse if the muscle CK isoform is overexpressed and a faster response if mitochondrial CKis overexpressed. The CK system is very effective in decreasing maximum levels of ADP duringsystole and reducing average P_i levels over the whole cardiac cycle.