IL-1 in the periphery plays a beneficial role in the skeletal muscle response to damaging exercise. With age, muscle adaptation to exercise become less robust and highly variable. We hypothesize that in some elderly individuals, impaired IL-1 induction may be responsible for the relatively weak hypertrophic response to exercise. On the other hand, although IL-1 and the inflammatory response appear to be required to initiate recovery from damaging exercise, this response must be limited or further muscle damage will ensue. We hypothesize that chronic over-expressing of IL-1 may lead to muscle wasting and even to an Alzheimer's disease-like pathology in muscle, analogous to including body myositis (IBM), where betaAPP is over-expressed and Abeta is deposited. Thus, relationships among IL-1 expression and genotype, betaAPP, and repair processes in muscle may parallel those observed in the brain. To test these hypotheses, in Specific Aim 1, we will determine whether there is a correlation among the muscle inflammatory response after an acute bout of resistant exercise, IL-1 abundance, and IL-1 genotype in the elderly. In Specific Aim 2, we will determine whether IL-1 expression and the inflammatory response after an acute exercise bout are predictive of the hypertrophic response of muscle from elderly individuals to chronic resistance training. Muscle fiber size and muscle mass will be quantitated, as well as the accumulation of IL-1, TNF-alpha, betaAPP, Abeta, and hyperphosphorylated tau (characteristic of IBM). This analysis will be combined with gene expression using cDNA microarrays to determine whether different IL-1 gene expression levels are associated with specific phenotypes in exercised muscle that may potentially contribute to frailty. In Specific Aim 2, we will study the interaction of IL-1 and betaAPP in muscle and myoblasts in vitro, using genetically modified animals. IL-1 levels will be manipulated in vivo and in muscle satellite cells in vitro to test the hypothesis that IL-1 over-expressing promotes a cascade of degenerative changes in muscle initiated by betaAPP. Identification of underlying molecular mechanisms regulating muscle adaptation to exercise and potentially contributing to muscle wasting during aging is vital to the development of effective interventive strategies to promote functional independence in the elderly.