RESUMEN
INTRODUCTION: Previous experiments have indicated that in vivo administration of ursodeoxycholic acid (UDCA) inhibits nuclear NF-κB activation and has beneficial effects on the structure and function of dystrophic (mdx) muscle. We examined the effect of UDCA on tension development in dystrophic muscle. METHODS: Isometric tension development was examined in costal diaphragms that were freshly isolated from vehicle and UDCA treated mdx mice. Percent recovery scores were obtained by directly comparing these measurements to those obtained from age-matched nondystrophic mice. RESULTS: Vehicle treated mdx mice exhibited significantly reduced optimal muscle lengths (lo ) and specific twitch and tetanic tensions compared with age-matched nondystrophic mice. UDCA treated preparations exhibited significantly improved tension development with a 33% recovery score. CONCLUSIONS: Because UDCA is used in treating certain clinical disorders, these results provide a rationale for human clinical trials using this and related drugs for treatment of Duchenne and related muscular dystrophies.
Asunto(s)
Diafragma/efectos de los fármacos , Inhibidores Enzimáticos/uso terapéutico , Distrofias Musculares/tratamiento farmacológico , Distrofias Musculares/patología , Ácido Ursodesoxicólico/uso terapéutico , Animales , Biofisica , Diafragma/fisiopatología , Modelos Animales de Enfermedad , Estimulación Eléctrica , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos mdx , Contracción Muscular/efectos de los fármacos , Distrofias Musculares/genéticaRESUMEN
The whole body tension (WBT) method was used to evaluate the hypothesis that long term treatment with NF-kappaB inhibitors improves the total forward pulling tension exerted by the limb musculature of the mdx mouse. Mdx mice exhibited significantly reduced WBT values and more profound weakening during the course of generating multiple forward pulling movements than age-matched nondystrophic mice. Long term treatment with the NF-kappaB inhibitor pyrrolidine dithiocarbamate (PDTC) did not significantly reduce nuclear p65 activation in the costal diaphragm, but increased WBT by 12% in mature (12 month) mice. Daily treatment (30 days) of 1 month old mdx mice with the inhibitor ursodeoxycholic acid (UDCA) reduced costal diaphragm nuclear p65 activation by 40% and increased WBT by 21%. These results indicate that treatment with NF-kappaB inhibitors improves WBT in the mdx mouse and further establishes the utility of the WBT procedure in assessing therapeutic efficacy.