The process of aging is accompanied by a gradual decline in the performance of most organ systems. The decreased mass and functional capability of skeletal muscles contribute largely to the impairment of locomotive performance that accompanies aging in both animals and humans. Although age-related degeneration in muscle functions has been amply documented, the molecular mechanisms underlying; selective muscle fiber atrophy in aging mammals are currently unknown, and therefore therapeutic courses aimed at maintaining functional and regenerative capacities in aging muscles have been difficult to design. The present study will directly address the molecular basis of age-related atrophy in mammalian skeletal muscle by investigating the function of a novel gene, c-ski, in the selective maintenance of muscle fiber size, composition, and regenerative capacity. Transgenic mice carrying extra copies of the c-ski gene display cell hypertrophy of precisely those muscle fibers which are most dramatically affected during the aging process. Our recent identification of a fiber-specific gene (myosin light chain) as the first known genetic target for ski action in skeletal muscle cells has prompted the experimental course outlined in this application. The first part of the project will draw upon our extensive knowledge of myosin light chain gene regulation, as well as the characterization of mouse lines both carrying ski and myosin light chain transgenes, to build a molecular model for the hypertrophic effects of ski gene expression, both in muscle cell culture and in the aging animal. This model will provide the basic information for our long-term research goal, to design a gene therapeutic approach aimed at maintaining the integrity of the skeletal muscle system in old age. The second part of the project exploits our experience with analysis of gene expression and transgenic mouse technology, in collaborative efforts with several laboratories. Together we will assess the potential effects of candidate longevity assurance genes on the development and aging of transgenic animals, focussing our own analysis on the skeletal musculature. Specifically, we will generate transgenic mice carrying the mammalian homolog of LAG1, the first cloned longevity assurance gene in yeast, and putative mammalian homologs to Drosophila LAGs as they are identified. Characterization of these mice will provide insights into the function of LAGs during development and in different tissues, and will potentially comprise a valuable model for further study of genetic parameters of longevity in mammals.
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