The involvement of glutathione in the adaptive response of skeletal muscle following repetitive, high-intensity mechanical loading is not known. PURPOSE: The purpose of this research was to examine the influence that dietary supplementation of a glutathione antagonist (L-Buthionine Sulfoximine (BSO)) has on skeletal muscle adaptation during chronic high-intensity mechanical loading via stretch-shortening contractions (SSCs) in young and old rodents. METHODS: Left dorsiflexor muscles of young (3 months, N= 16) and old (30 months, N = 16), vehicle- and BSO-treated rodents were exposed 3 times per week for 4.5-weeks to a protocol of 80 maximal SSCs per exposure in vivo. Skeletal muscle response was characterized by muscle wet-weight and quantitative morphological analyses following the exposure period. RESULTS: Muscle-wet weight was increased following loading of the exposed limb compared with the contra-lateral control limb, irrespective of age. Further, young rodents had significantly increased muscle wet-weight compared to old rodents. No degenerative myofibers were noted in either age group, but a significant increase was observed in the volume of non-cellular interstitium, indicative of edema, as a result of aging. Muscle cross-sectional area increased in the young, vehicle rodents (a shift from 46% to 68% of Fibers >=2,000 um2), and in old, vehicle rodents (a shift from 50% to 62% of fibers >= 2,000 um2); glutathione depletion had no additional affect on muscle area. CONCLUSIONS: Even though muscle area changes are observed with old rodents, aging negatively influences the adaptive response to chronic SSC exposure by limiting performance as well as morphological adaptation compared with young counterparts; however glutathione depletion does not adversely affect nor exacerbate this adaptive profile.