Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy
Document Type
Article
Abstract
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-kappaB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKbeta in mdx mice elucidated that NF-kappaB functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-kappaB in the progression of muscular dystrophy and suggest the IKK/NF-kappaB signaling pathway as a potential therapeutic target for DMD.
Medical Subject Headings
Animals; Disease Models, Animal; Disease Progression; Gene Deletion; Humans; I-kappa B Kinase (metabolism); Macrophages (physiology); Mice; Mice, Knockout; Muscle Fibers, Skeletal (physiology); Muscle, Skeletal (physiopathology); Muscular Dystrophy, Duchenne (genetics, physiopathology, therapy); NF-kappa B (physiology); Signal Transduction (physiology); Transcription Factor RelA (genetics)
Publication Date
4-1-2007
Publication Title
The Journal of clinical investigation
ISSN
0021-9738
Volume
117
Issue
4
First Page
889
Last Page
901
PubMed ID
17380205
Digital Object Identifier (DOI)
10.1172/JCI30556
Recommended Citation
Acharyya, Swarnali; Villalta, S Armando; Bakkar, Nadine; Bupha-Intr, Tepmanas; Janssen, Paul M.; Carathers, Micheal; Li, Zhi-Wei; Beg, Amer A.; Ghosh, Sankar; Sahenk, Zarife; Weinstein, Michael; Gardner, Katherine L.; Rafael-Fortney, Jill A.; Karin, Michael; Tidball, James G.; Baldwin, Albert S.; and Guttridge, Denis C., "Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy" (2007). Translational Neuroscience. 1391.
https://scholar.barrowneuro.org/neurobiology/1391