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Activation of nuclear factor‐kappa B protects dystrophin‐deficient muscle fibers from apoptosis
Author(s) -
Dogra Charu,
Wergedal Jon,
Kumar Ashok
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1087-b
Subject(s) - skeletal muscle , mdx mouse , endocrinology , medicine , duchenne muscular dystrophy , dystrophin , apoptosis , chemistry , iκb kinase , nf κb , nfkb1 , tunel assay , biology , microbiology and biotechnology , transcription factor , biochemistry , gene
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.