Activation of nuclear factor‐kappa B protects dystrophin‐deficient muscle fibers from apoptosis

Abstract

Nuclear factor-kappa B (NF-κB) is a major transcription factor involved in host immune and inflammatory responses and protection from apoptosis. Here, we have investigated the role and the mechanisms of activation of NF-κB in dystrophin-deficient skeletal muscles. Intramuscular injection of NF-κB reporter plasmid showed higher transcriptional activity of NF-κB. Muscle-specific transgenic expression of IκBα N (a super repressor form of IκBα) in mdx mice (Tg/mdx) inhibited NF-κB activity. Inhibition of NF-κB in mdx mice exaggerated muscle pathogenesis as evident by increased serum creatine kinase (CK) activity in Tg/mdx mice compared to littermate mdx mice. Histological analysis of diaphragm muscles showed increased variability in fiber size, central nucleation, and injury of Tg/mdx myofibers compared to littermate mdx mice. The extent of fibrosis in diaphragm muscle was higher in Tg/mdx mice compared to littermate mdx mice. The levels of NF-κB regulated anti-apoptotic molecules, such as Bcl-2, and cIAP1 were also reduced in Tg/mdx myofibers. Furthermore, analysis of muscle fibers using TUNEL assay revealed increased apoptosis in Tg/mdx mice. Pretreatment of diaphragm muscles with LY294002 (an inhibitor of PI3K) inhibited the DNA-binding activity of NF-κB, suggesting involvement of PI3K/Akt signaling pathway in the activation of NF-κB in mdx skeletal muscles.