imd-0354 and Muscular-Dystrophy--Duchenne

Activated fibroblasts continue to proliferate at injury sites, leading to progressive muscular fibrosis in Duchenne muscular dystrophy (DMD). TGF-β1 is a dominant profibrotic mediator thought to play a critical role in muscle fibrosis; however, the implicated mechanisms are not fully understood. Here we showed that TGF-β1 increased the resistance to apoptosis and stimulated cell cycle progression in dystrophic muscle fibroblasts under serum deprivation conditions in vitro. TGF-β1 treatment activated the canonical NF-κB pathway; and we found that pharmacological inhibition of IKKβ with IMD-0354 and RelA gene knockdown with siRNA attenuated these effects of TGF-β1 on dystrophic muscle fibroblasts. Collectively, our data suggest that TGF-β1 prevents apoptosis and cell cycle arrest in dystrophic muscle fibroblasts through the canonical NF-κB signaling pathway.

Topics: Animals; Apoptosis; Benzamides; Cell Proliferation; Cell Survival; Fibroblasts; I-kappa B Kinase; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Dystrophy, Duchenne; NF-kappa B; RNA, Small Interfering; Signal Transduction; Transcription Factor RelA; Transforming Growth Factor beta1