Skeletal muscle represents the major repository of body protein. In addition to its functional role, skeletal muscle provides amino acids for processing by visceral organs during stress. Hypermetabolism and accelerated net breakdown of lean body mass characterize the early metabolic response to significant injury or infection. We hypothesize that changes in muscle high energy metabolism at rest, during exercise, and recovery from exercise can be used to describe the effect of sepsis on skeletal muscle energetics. Phosphorus and sodium nuclear magnetic resonance spectroscopy (31P and 23Na NMR) will be used to study the effects of sepsis on gastrocnemius muscle high energy phosphate metabolism and membrane function in the rat and in a perfused muscle preparation. Changes in membrane function will be assessed in vivo by monitoring changes in the distribution of extracellular and intracellular sodium using sodium spectroscopy and in vitro by measuring changes in total and Na-K ATPase activity. The non-invasive measurements of phosphorus-31 and sodium-23 will be used to determine the relationship between high energy phosphate metabolism, oxidant injury, and endotoxin or tumor necrosis factor (TNF) as potential mediators of these effects. The relative quantities of ATP, phosphocreatine, and inorganic phosphate and intracellular and extracellular sodium will be determined (using NMR spectroscopy and in vitro assays). The rate of reconstitution of the high energy phosphate pool will be monitored before, during and after standard work loads. NMR techniques will be used to measure forward and reverse flux through the creatine kinase pathway in vivo. These measurements will be used to determine the effects of sepsis on phosphocreatine breakdown and resynthesis rates via this pathway. NMR techniques will also be used to measure pH and the phosphorylation potential, and to calculate free ADP concentrations and changes in the free energy hydrolysis of ATP as indices of the cellular energy state. The effect of maximizing oxygen delivery using volume expansion, inotropes, and topical and parenteral anti-oxidant therapy will be assessed. These studies will increase our understanding of the relationship between changes in high energy phosphate metabolism, membrane pump function, potential mediators of the observed changes (endotoxin, TNF), and therapeutic interventions in animal models. We will then determine the validity of these relationships in surgical patients.
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