For humans, frailty constitutes of one of the most prominent and consistent features of aging andrepresents the summation of the effects of muscle atrophy and weakness. For the elderly, physical frailtycontributes to impaired mobility, a high risk of falling, an increased incidence of muscle injury, and adecreased quality of life. Despite considerable effort over the past decade, little progress has been madein lessening the magnitude of the problem. During our first five years of support, research on a dozen ormore varieties of knockout and transgenic mice, this Program Project identified the Sodl^' mouse as ahighly promising model to test the working hypothesis of Project 1 that age-related skeletal muscleatrophy results from a decrease in the total number of motor units caused by increasedsuperoxide-mediated oxidative stress in neurons and muscles, such that: (i) oxidative stress inneurons initiates a loss of motor neurons, impairs axonal sprouting from surviving motorneurons, and inhibits nerve regeneration; and (ii) oxidative stress in muscles fibers inhibits reinnervationand contributes to decreased contractility of innervated muscle fibers. The workinghypothesis will be tested through experiments on SodfA and Sod1+/+ mice, transgenic Socf7v' mice withSod1 expression rescued only in nerves (Soc/fA(N+) mice) or muscles (Soc(7~/~(M+) mice), and tissue-specificknockout mice that lack CuZnSOD activity only in nerves (Sod1A3,4N)N) or muscles (Sod 1 A3,4^). Thesemodels allow us to test hypotheses regarding the contribution of systemic oxidative stress, as well astissue-specific oxidative stress on the structure and function of motor nerves, muscles, motor units andmuscle fibers. Genetically modified mice will be studied at 6-8 months and 18-20 months, whereasSod1+/+ mice will be studied at 6-8, 18-20, and 28-30 months. Unique aspects of the proposed studies arethe determination of motor unit properties and contractility of permeabilized single fibers from Soc/f/'mice,,null mice with tissue-specific rescue, and tissue-specific Sodl knockout mice. Furthermore, studies of therelative timing of changes in nerves and muscles that have not been undertaken previously in the sameanimals will be particularly illuminating for establishing cause-effect relationships of age-related changesin the neuromuscular system. Along with Projects 2 and 3, studies utilizing the very powerful mousemodels listed above will determine the mechanistic role of superoxide-induced oxidative stress in musclesand nerves in age-related skeletal muscle atrophy. The Public Health significance is the necessity tounderstand the mechanisms underlying age-associated skeletal muscle atrophy and weakness to providethe basis for health professionals to design and implement scientifically based strategies to ensure'successful aging' by reducing and perhaps even eliminating physical frailty in the elderly population.
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