Sarcopenia, the age-related decline of muscle mass and strength, is one major risk factor for frailty and mobility disability of the elderly. Muscle disuse due to bed rest or surgery (such as joint replacements) exacerbates the ongoing decline of muscle function in the elderly. The decline of muscle function with disuse is greater in aging muscles. However, the cellular mechanism responsible for the greater functional decline of aging muscles with disuse is unknown. Oxidative stress, a condition where the balance between oxidant production and removal is disrupted, is a shared mechanism of age and disuse related muscle dysfunction. Thus, the overall aim of my dissertation is to understand the role of oxidative stress in the age-related muscle dysfunction with disuse.Using an animal model of muscle disuse (hindlimb unloading), I tested the hypothesis that the ability of aging muscles to cope with the increased oxidative stress associated with muscle disuse is compromised. There are three major findings: (1) the regulation of glutathione (GSH), an essential endogenous antioxidant, is impaired in aging muscles with disuse; (2) the decline of GSH levels in aging muscles with disuse is associated with the decrease of glutamate cysteine ligase (GCL) activity and the reduction of the catalytic subunit of GCL content; (3) using proteomic techniques, I identified two proteins (carbonic anhydrase III and four-and-a-half LIM protein1, FHL1), which show changes in the oxidation levels with disuse and aging. The changes in the oxidation levels of these two proteins with disuse occur in adult rats but not old rats. However, old rats have greater baseline levels of oxidized FHL1.In summary, the series of studies demonstrate that the response of muscles with disuse is age-dependent. The ability to maintain GSH levels with disuse is compromised in aging muscles. In addition, the changes of protein oxidation with muscle disuse occur in specific proteins and that the changes are age-related.