This project is concerned with elucidating energy metabolism, especially the formation, transfer, and use of high-energy phosphate (creatine and adeninenucleotides) in heart and skeletal muscle. We will further develop existing computer models of this metabolism, and methods for their analysis and construction. Microcomputers and collaboration between modelers and experimenters who re using the models on their own laboratory microcomputers will be emphasized, with the objective of making the models and techniques generally available to interested experimenters. We will use data from both nuclear magnetic resonance (NMR) and conventional chemical analyses, combining apparently divergent information (including viewpoints and definitions) from both sources, and deal with current inadequacies of methods of interpreting NMR experiments. Initially we will emphasize creatine kinase and the creatine kinase shuttle with phosphorus-31 NMR, by modeling and designing experiments. We will also improve methods of calculating exchange by enzymes and apply them to saturation-transfer measurements. We will examine control of the glycolytic pathway, with which we are experienced, emphasizing regulation by adenine nucleotides and magnesium ion. We will construct or adapt simple models of oxidative phosphorylation, the principal energy source of normal heart. We will complete, update, extend to other experimental conditions (e.g., blood-perfused heart, observable with in situ NMR), and validate as far as possible a nearly completed unified model of cardiac energy metabolism, now representing 13 experimental preparations or conditions and about 1500 data points from rat and dog hearts. We will also determine its control properties by sensitivity analysis, and then devise means of simplifying it or subsetting it for particular conditions or purposes. A parallel muscle model, with nearly the same enzyme subunits in different amounts, will be used to investigate the same metabolism in muscle. We will extend or construct data bases containing data needed for this work. We will update, document, distribute, and maintain the required computer programs and (as far as is now possible) the models used.
