RESUMO
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.
Assuntos
Tono Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , NF-kappa B/antagonistas & inibidores , Pirrolidinas/farmacologia , Tiocarbamatos/farmacologia , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Colagogos e Coleréticos/farmacologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos mdx , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Exercícios de Alongamento Muscular/efeitos adversos , Tono Muscular/fisiologia , Debilidade Muscular/tratamento farmacológico , Debilidade Muscular/metabolismo , Debilidade Muscular/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/metabolismo , Distrofia Muscular de Duchenne/fisiopatologia , NF-kappa B/metabolismo , Pirrolidinas/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Tiocarbamatos/uso terapêutico , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismo , Resultado do Tratamento , Ácido Ursodesoxicólico/farmacologia , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
Dystrophin-deficient muscle exhibits substantial increases in nuclear NF-kappaB activation. To examine potential mechanisms for this enhanced activation, the present study employs conventional Western blot techniques to provide the first determination of the relative expression of NF-kappaB signaling molecules in adult nondystrophic and dystrophic (mdx) skeletal muscle. The results indicate that dystrophic muscle is characterized by increases in the whole cell expression of IkappaB-alpha, p65, p50, RelB, p100, p52, IKK, and TRAF-3. The proportion of phosphorylated IkappaB-alpha, p65, NIK, and IKKbeta, and the level of cytosolic IkappaB-alpha, were also increased in the mdx diaphragm. Proteasomal inhibition using MG-132 increased the proportion of phosphorylated IkappaB-alpha in nondystrophic diaphragm, but did not significantly increase this proportion in the mdx diaphragm. This result suggests that phosphorylated IkappaB-alpha accumulates in dystrophic cytosol because the rate of IkappaB-alpha degradation is lower than the effective rate of IkappaB-alpha synthesis and phosphorylation. Dystrophic increases in SUMO-1 (small ubiquitin modifier-1) protein and in Akt activation were also observed. The results indicate that increases in nuclear p65 activation in dystrophic muscle are not produced solely by increases in the activity of IkappaB-alpha kinase (IKK), but are due primarily to increases in the expression of p65 and other NF-kappaB signaling components.