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Skeletal muscle protein and function decline with advancing age but the underlying pathophysiology is poorly understood. To test the hypothesis that the catabolic cytokine tumor necrosis factor alpha (TNF-α) contributes to this process, we studied the effects of aging and resistance exercise on TNF-α expression in human muscle. Using in situ hybridization, TNF-α message was localized to myocytes in sections of skeletal muscle from elderly humans. Both TNF-α mRNA and protein levels were elevated in skeletal muscle from frail elderly (81±1 year) as compared to healthy young (23±1 year) men and women. To determine whether resistance exercise affects TNF-α expression, frail elderly men and women were randomly assigned to a training group or to a nonexercising control group. Muscle biopsies were performed before and after 3 months. Muscle TNF-α mRNA and protein levels decreased in the exercise group but did not change in the control group. Muscle protein synthesis rate in the exercise group was inversely related to levels of TNF-α protein. These data suggest that TNF-α contributes to age-associated muscle wasting and that resistance exercise may attenuate this process by suppressing skeletal muscle TNF-α expression.