Recent evidence obtained in this laboratory indicates that treatments which reduce the nuclear activationof the transcription factor nuclear factor-kappaB (NF?B) have distinct beneficial effects in substantially reducingthe loss of striated muscle fibers and restoring the resting membrane potential in severely dystrophic (mdx)muscle fibers [2]. These results indicate a clear need for investigating the potential clinical utility of NF?Binhibitors in treating Duchenne and Becker muscular dystrophies. The purpose of these proposed studies is todetermine the clinical utility of sulfasalazine which inhibits the NF?B pathway in dystrophic muscle. Sulfasalazineis of particular interest because it is currently used on a chronic basis to treat inflammatory disorders in bothadults and children. Undergraduate, graduate, and D.O. students (A.T. Still University, Truman State University)will be involved in assessing the effects of sulfasalazine treatment on tension development in two isolated mdxmuscles (gastrocnemius, costal diaphragm) and on whole body strength in intact mdx mice. This study is done inparallel with translational investigations that include assessments of cytosolic and nuclear levels of NF?B inchronically treated mdx muscle, the expression of inflammatory cytokines in plasma and muscle extracts, restingmembrane potential, plasma creatine kinase levels, skeletal muscle fibrosis, and histological determinations of thetotal number of fibers, the proportion of striated vs necrotic fibers, percent centronucleation, and the distribution offiber diameter and cross sectional areas in dystrophic mdx muscle. The proposed studies will test the specifichypothesis that sulfasalazine treatment improves muscle function in the mdx mouse and will provide essentialpre-clinical information that can be used in clinical trials for patients with Duchenne and Becker musculardystrophies. PROJECT NARRATIVEThese studies will examine the potential therapeutic efficacy of sulfasalazine which is a member of a class ofdrugs (NF?B inhibitors) that have recently been shown to have beneficial effects in the mdx mouse, a modelfor Duchenne muscular dystrophy. Sulfasalazine is currently used to treat inflammatory conditions in bothchildren and adults, and the results of the proposed investigations will provide critical information forestablishing clinical trials to test the efficacy of sulfasalazine in treating patients with Duchenne and Beckermuscular dystrophy.
