This proposal focuses on the regulation of energy balance in fast and slow skeletal muscles in order to determine mechanisms of regulation of oxidative phosphorylation that presumably operate in all cell types. The premise for this work is that kinetic expressions for existing data are phenomenological rather than mechanistic. In order ultimately to develop a detailed kinetic equation for oxidative phosphorylation, the applicant proposes to undertake a detailed thermodynamic analysis of forces and flows in muscles. Flows in this system are the rates of ATP synthesis and oxygen consumption, while forces are the cytoplasmic chemical potential of ATP (GP) and the redox potential of NADH (Gredox). Both slow and fast muscles will be studied since terms for GP predominate in fast muscles, while a composite of GP and Gredox operate in slow muscles. Experiments will address three fundamental questions: 1. What is the scope of regulation in cellular respiration? The range of normal operation for oxidative phosphorylation and energy balance will determined in order to assess physiological fluxes (J) as a fraction of maximal flux (Jmax). 2. Are the physiological functional ranges of these fluxes also the maximum? This idea will be tested by extending the thermodynamic analysis beyond the physiologically accessible range, which will involve manipulating GP and Gredox. 3. What is the kinetic equation(s) for regulation? This question will be addressed by defining and testing the rate equation for mitochondrial ATP synthesis applicable to each muscle type.
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