Successful gene therapy of Duchenne muscular dystrophy may require the lifelong expression of a therapeutic gene in all affected muscles. The most promising gene delivery vehicles, viral vectors, suffer from several limitations, including immunogenicity, loss of therapeutic gene expression, and a limited packaging capacity. Therefore, various efforts were previously undertaken to use small therapeutic genes and to place them under the control of a strong and muscle-specific promoter. Here we report the effects of a minidystrophin (6.3 kb) under the control of a short muscle-specific promoter (MCK 1.35 kb) over most of the lifetime (4-20 months) of a transgenic mouse model. Dystrophin expression remained stable and muscle-specific at all ages. The dystrophic phenotype was greatly ameliorated and, most importantly, muscle function in limb muscles was significantly improved not only in young adult but also in aged mice compared to nontransgenic littermates. Dystrophin expression was strong in fast-twitch skeletal muscles such as tibialis anterior and extensor digitorum longus, but weak or absent in heart, diaphragm, and slow-twitch muscles. Additionally, expression was strong in glycolytic but weak in oxidative fibers of fast-twitch muscles. This study may have important implications for the design of future gene therapy trials for muscular dystrophy.