TIMP-2 is expressed by motor neurons and in the basal lamina of muscle fibers. In muscle, TIMP-2 is expressed at higher levels in fast-twitch fibers where it co-localizes with β1 integrin at costameres, the structures that link the myofiber contractile apparatus to the ECM. Using a variety of techniques, including the RotaRod, to test motor function we demonstrated that TIMP-2^-/- mice exhibit profound hyperkinesia as juveniles and motor weakness as adults. Gelatinase MMP activity is reduced in TIMP-2^-/- mice. In addition, β1 integrin expression is decreased in fast-twitch fibers. Studies are in progress to determine the mechanism by which TIMP-2 regulates β1 integrin expression. As a small secreted protein, it would be easier to develop TIMP-2, than the transmembrane proteins dystrophin or β1 integrin, as a therapeutic for age-related muscle weakness and muscular dystrophy.