Maintenance of tissue adenine nucleotide (AdN - ATP+ADP+AMP) concentration is universally important because of AdN interactions in a broad range of cellular processes. This is especially true in skeletal muscle where the rate of ATP hydrolysis can increase may fold. Processes important for AdN homeostasis in contacting muscle include: 1) the control of energy supply pathways, especially mitochondrial respiration, to meet the energy demands of contractions; 2) AdN degradation reactions, especially acting on AMP times of energy imbalances; 3) AdN recovery reactions involving de novo synthesis and purine salvage pathways; ad 4) contractile function, which determines ATP hydrolysis rate. An isolated perfused rat hindlimb muscle preparation will be used to evaluate how these factors affecting AdN metabolism are a) interdependent, b) different between muscle fiber types, c) subject to adaptations, and d) modified in certain disease states. The metabolic and functional significance of AdN degradation to purine nucleotides, nucleotides and bases in fast-twitch and slow-twitch muscle will be determined during and following intense exercise. Muscle and plasma AdN and degradation products are determined by HPLC analyses. The physiological significance of the 10-20% loss in ATP pool, that does not appear as AdN degradation products in slow-twitch muscle, will be sought. Subsequent recovery of AdN via de novo synthesis and purine salvage pathways will be determined using labeled precursors. The influence that factors controlling respiration have on AdN degradation will be assessed in muscle differing in mitochondrial content and phosphocreatine content. These novel studies will provide fundamental informational important for the understanding of AdN metabolism in the various fiber types of normal muscle. This information in turn, should greatly increase our understanding of abnormalities in AdN metabolism found in certain myopathies, and the potential consequences of related muscle enzyme deficiencies.
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