To understand how exercise affects the contractile function of dystrophic muscle, we examined the effect of long-term voluntary exercise onmdxmice and related these effects to our findings in sedentary aging mice. Although the mdx mouse is the genetic homolog for Duchenne muscular dystrophy, it does not demonstrate the same progression in limb muscle dysfunction as Duchenne muscular dystrophy as it ages. We postulated that the sedentary lifestyle of this animal plays an important role in its minimal phenotypic expression. To examine the effect of exercise, eight C57BL/10 (C57) and eightmdxmice were allowed to run ad libitum for one year. Forty sedentarymdxmice and 40 sedentary C57 from one month to 18 months of age were used as controls. Contractile characteristics of the extensor digitorum longus and soleus muscles and morphometric characteristics of the mice were examined. Themdxmice ran approximately 45% fewer kilometers per day than C57 mice. Long-term voluntary running had beneficial training effects on both the oldmdxmice and their C57 controls. The exercise ameliorated the age-associated loss in tension production that was observed in the soleus of sedentarymdxand sedentary C57 mice. There was a 9% reduction in the fatigability of the extensor digitorum longus muscle of the oldmdxmice after the exercise. Despite these improvements, the oldmdxmice exhibited significant functional deficits compared with their C57 controls. Our hypothesis, that long-term voluntary exercise would have a beneficial training effect on control mice and a deleterious effect onmdxmice as they aged, was not supported by this study. This study shows that dystrophin-less muscles from sedentary mice display significant signs of muscle damage, yet can respond beneficially to low-level voluntary running in a manner similar to that of the C57 control.