The long term goals of this research are to understand the control of mitochondrial ATP production in heart during changes in cardiac work in normal and pathological states. A number of heart diseases such as ischemia and hypertrophy are associated with defects in energy metabolism. This work relies on the application of NMR, to monitor levels of key metabolites, and molecular genetic techniques, to produce transgenic mice with alterations in energy metabolism. The immediate aims of the proposed research are to use a transgenic mouse model expressing creatine kinase in liver to determine the relation between extra mitochondrial ADP, mitochondrial NADH, and oxygen consumption in vivo. These data will be used to test the hypothesis that hormone stimulation of oxidative ATP production occurs due to increases in mitochondrial NADH. In addition, experiments will be performed to understand the role of creatine kinase, an abundant cardiac enzyme, in cellular energetics. A transgenic mouse expressing mitochondrial creatine kinase in liver will be produced. The effects of mitochondrial creatine kinase on the control of oxidative ATP production will be assessed. Finally, a set of transgenic mice with an altered creatine kinase isoenzyme distribution will be studied to see if alteration of creatine kinase affects muscle energy metabolism.
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