The long-term objective is to develop therapeutic strategies directed at satellite stem cells that will preserve muscle mass in the elderly. Satellite stem cells are the major source of adult skeletal muscle regeneration, and so, are important targets for preserving skeletal muscle mass in the elderly. Long known as muscle progenitors, cultured satellite stem cellscan also generate other daughter cell types, including adipocytes (fat cells). This pluripotentiality of satellite stem cells suggests that they may play a direct role in changing the phenotype of skeletal muscle, especially in the elderly. Satellite cell-derived adipogenesis in tissue culture is promoted by a high (20%) oxygen (O2) environment, conducive to production of reactive oxygen species (ROS), an environment that mimics the oxidative stress of old skeletal muscle. In lower (6%) O2 culture conditions satellite stem cells are much less likely to undergo adipogenesis. These phenotypic findings have important molecular correlates: Analysis of single satellite stem cells reveals that high O2/ROS induces increased expression of genes that promote fat development, while low O2 conditions are associated with up-regulation of genes that promote muscle development and differentiation. High O2/ROS induces increased expression of genes that promote fat development, while low O2 conditions are associated with up-regulation of genes that promote muscle development and differentiation. High O2/ROS culture conditions also decrease satellite cell proliferation, and this defect is pronounced in satellite stem cells derived from old mice vs. those derived from young/adult mice. Thus, aging associated ROS-induced reduction in proliferation as well as adipogenesis may remove satellite stem cells from the myogenic pool and directly contribute to the characteristic pathology of muscle aging, which is a loss of muscle mass and accumulation of muscle lipid. These data suggest that the loss of muscle with aging is more than a degenerative phenomenon, and that satellite stem cells may undergo age-associated pathologic regeneration. The working hypothesis is that the imbalance between ROS accumulation and decreased antioxidant function in old muscle induces specific gene expression patterns in satellite stem cells that result in their defective proliferation, apoptosis and myogenic differentiation when compared to satellite stem cells from young/adult animals. Proliferation, apoptosis, and differentiation patterns will be quantitated and compared for satellite stem cells from old vs. young/adult mice, and from old wild type mice vs. old antioxidant-deficient mouse models. In parallel to these cellular assays, expression patterns of satellite stem cells will be compared for these different groups with the goal of identifying potential therapeutic protein products that increase survival, proliferation and myogenic differentiation of satellite stem cells in old animals.
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