TY - JOUR T1 - Analyzing the Functional Properties of the Creatine Kinase System with Multiscale ‘Sloppy’ Modeling A1 - Hettling, Hannes A1 - van Beek, Johannes HGM Y1 - 2011/08/11 N2 - Author Summary Creatine kinase (CK) has several functions in cellular energy metabolism. It catalyzes the reversible transfer of high-energy phosphate from ATP to creatine, facilitating storage of energy in the form of phosphocreatine. In muscle cells, this extra energy buffer plays a pivotal role in maintaining ATP homeostasis. Another proposed function of CK is the transport of energy from ATP producing to ATP consuming sites via a shuttle mechanism involving a mitochondrial and a myofibrillar isoform of CK. The extent to which this ‘phosphocreatine shuttle’ mechanism is used in muscle and other tissues is hotly debated. We use a computational model of the CK system which can predict energy transport and buffering of high demand peaks to estimate the relative importance of both roles in heart muscle. We validate the model with multiscale data on the level of enzyme kinetic constants and with dynamic oxygen consumption measurements in rabbit hearts. Since model predictions can be strongly affected by changes in parameter values, we employ ‘sloppy’ ensemble modeling which allows to set confidence regions for predictions. Our results indicate that the main function of CK in heart muscle lies more in temporal energy buffering of high peaks in ATP consumption during cardiac contraction than in energy transportation. JF - PLOS Computational Biology JA - PLOS Computational Biology VL - 7 IS - 8 UR - https://doi.org/10.1371/journal.pcbi.1002130 SP - e1002130 EP - PB - Public Library of Science M3 - doi:10.1371/journal.pcbi.1002130 ER -