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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 7

Muscle progenitor cells increase in mice lacking IKKβ.

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Muscle progenitor cells increase in mice lacking IKKβ.
Gastrocnemius or ...
Gastrocnemius or quadriceps were harvested from 4-week-old mdx;IKKβF/F and mdx;IKKβF/F;MLC-Cre mice and frozen for RNA analysis (A), cryosectioned (B), or homogenized for immunoblotting (C). (A) Real-time PCR analysis of CD68, TNF-α, IL-1β, MCP-1, RANTES, and MIP-1α (macrophage inflammatory protein 1α) obtained from 3–6 mice per group. (B) Sections as described in A or from 7-week-old mdx;p65+/+ and mdx;p65+/– mice were immunostained with MyoD and quantitated from a minimum of 20 randomly chosen fields per section in 3–4 animals per group. (C) Western blots probing for Pax7 and α-tubulin. (D and E) Satellite cells were isolated from pooled hind limb muscles from 4-week-old mdx;IKKβF/F and mdx;IKKβF/F;MLC-Cre littermates and either fixed and stained with Pax7 or differentiated for 3 days and subsequently stained with MyHC to determine myotube number normalized per mm2 area. Scale bars: 200 μm. (F) Flow-cytometric analysis from freshly isolated cells of 4-week-old mdx;IKKβF/F and mdx;IKKβF/F;MLC-Cre mice were stained with cell-surface markers CD34 and Sca-1. Graph represents averages from 2 independent experiments. Data are plotted as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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Referenced in 12 patents
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