In this renewal, we are proposing to extend our studies of mtDNA abnormalities in aging processes. Our efforts have focused on rodent skeletal muscle, demonstrating that age-associated mtDNA deletions accumulate to high levels in a subset of muscle fibers and are associated with ETS abnormal regions of the fibers. These ETS abnormal regions typically lacked complex IV activity (cytochrome c oxidase; some subunits of which are mtDNA-encoded) while being hyperreactive for complex II (succinate dehydrogenase; which is entirely nuclear-encoded). The characterization of ETS abnormal fibers along their length identified regions which dramatically decreased in cross sectional area suggesting an association between deleted mtDNAs, ETS abnormalities, and fiber atrophy. Our objective is to further characterize age-associated ETS abnormal regions and the associated atrophy of skeletal muscle fibers. Since ETS abnormal regions are segmental, these experiments require the characterization of muscle fibers along their length. Five muscles, three of which exhibit age-associated atrophy, will be characterized in F344 x BNF1 rats of various ages (adult to advanced old age). These studies will involve measures of sarcopenia (muscle mass, fiber number and fiber area) combined with histologic analyses of ETS activity and presence of deleted mtDNAs. We will, in addition, address the fate of ETS abnormal fibers through the analysis of fiber area as well as cellular indicators of fiber death (apoptosis and necrosis).
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