and Specific Aims.) Atrophy of skeletal muscle in humans begins in the third decade of life, but its functional significance is not realized until many decades later (when elderly people have reductions in skeletal muscle mass and strength below that required for independence in daily activities).The mechanisms of the aging- associated atrophy of skeletal muscle have not been established.However, strength training, such as weight lifting, can prevent the loss of muscle mass between the ages of 50-70 years (before senescence) in humans. A component of strength training, eccentric exercise (lengthening contractions), increases insulin-like growth factor-I (IGF-I) immunoreactivity within muscle fibers of young rats. Increases in IGF-I peptide and mRNA have been shown to be associated with muscle hypertrophy in tissue culture and in the work overload model, respectively. Conversely, IGF-I mRNA is decreased in skeletal muscle of young rats when the muscle was not allowed to support the load of body weight (which could be analogous to the decreased mobility or activity by older people). Thus, a potential relationship between weight-bearing exercise, IGF-I expression, and muscle size is suggested.
Four Specific Aims will be tested. First, is the IGF system different between senescent and adult muscle? Does aging reduce the IGF system concurrent with atrophy of skeletal muscle? Measurements include mRNAs for IGFs and insulin- like growth factor binding proteins (IGFBPs), secretion of IGFs and IGFBPs from muscle, and receptor binding densities for IGF and growth hormone on muscle. Second, does the IGF system respond to a given bout of exercise differently between adult and senescent rats? Can eccentric exercise increase the IGF system in senescent muscle?Third, does senescent muscle have an insufficient IGF system to allow major regrowth from prior atrophy? Fourth, can the implantation of neonatal satellite cells, either with or without constitutive expression of IGF-I, into senescent muscle reverse the atrophy of senescent muscle? Does it take IGF-I peptide alone, or eccentric exercise alone, or both reverse atrophy in fast-type skeletal muscle between the ages of 21-24 months in Fischer 344 rats? These Specific Aims may help determine whether causal relationships exist between reductions in muscle activity, changes in IGF expression/modulation, and muscle atrophy in senescent rats. The potential significance of this application is that alterations of the IGF- I system will be tested as a possible mechanism for the atrophy of skeletal muscle with aging.
