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Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy
Swarnali Acharyya, … , Albert S. Baldwin, Denis C. Guttridge
Swarnali Acharyya, … , Albert S. Baldwin, Denis C. Guttridge
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):889-901. https://doi.org/10.1172/JCI30556.
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Research Article Inflammation Article has an altmetric score of 3

Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy

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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 IκB kinase/NF-κB (IKK/NF-κB) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-κB was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKKβ in mdx mice elucidated that NF-κB 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-κB in the progression of muscular dystrophy and suggest the IKK/NF-κB signaling pathway as a potential therapeutic target for DMD.

Authors

Swarnali Acharyya, S. Armando Villalta, Nadine Bakkar, Tepmanas Bupha-Intr, Paul M.L. Janssen, Micheal Carathers, Zhi-Wei Li, Amer A. Beg, Sankar Ghosh, Zarife Sahenk, Michael Weinstein, Katherine L. Gardner, Jill A. Rafael-Fortney, Michael Karin, James G. Tidball, Albert S. Baldwin, Denis C. Guttridge

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Figure 8

Pharmacological inhibition of IKK rescues the histopathology and function of dystrophic muscle.

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Pharmacological inhibition of IKK rescues the histopathology and functio...
(A) Amino acid sequence of WT or mutant (mut) NBD peptides. Underlined amino acids indicate changes from WT to mutant forms. (B) Soleus muscles from WT or mutant NBD–treated mice were stained with F4/80, and macrophages were quantitated. Scale bar: 300 μm. (C) Gastrocnemius muscles harvested from mdx mice treated for 4 weeks were sectioned and stained with either p-p65 (C) or H&E (E). Scale bars: 20 μm (C and E). (D) Lysates from mice were used for Western blots probing for p-p65, p65, and IκBα. (F) RNA was isolated from similar muscles as used for D including C57BL/10 and mdx controls, and real-time PCR was performed for lysozyme (n = 4). (G) Regeneration potential was measured by quantitating fibers with centronucleation and positive E-MyHC staining from mdx mice treated with saline or NBD peptides. (H) Force generation assessed by measuring active developed force comparing diaphragm muscles from mice treated with either WT or mutant NBD peptide for 4 weeks. Quantitative data are plotted as mean ± SEM from 3 independent experiments. *P < 0.05.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 12 patents
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