title: Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy.
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.
authors: Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
authors: Swarnali
authors: S
authors: Acharyya
authors: S Armando
authors: SA
authors: Villalta
authors: Nadine
authors: N
authors: Bakkar
authors: Tepmanas
authors: T
authors: Bupha-Intr
authors: Paul M L
authors: PM
authors: Janssen
authors: Micheal
authors: M
authors: Carathers
authors: Zhi-Wei
authors: ZW
authors: Li
authors: Amer A
authors: AA
authors: Beg
authors: Sankar
authors: S
authors: Ghosh
authors: Zarife
authors: Z
authors: Sahenk
authors: Michael
authors: M
authors: Weinstein
authors: Katherine L
authors: KL
authors: Gardner
authors: Jill A
authors: JA
authors: Rafael-Fortney
authors: Michael
authors: M
authors: Karin
authors: James G
authors: JG
authors: Tidball
authors: Albert S
authors: AS
authors: Baldwin
authors: Denis C
authors: DC
authors: Guttridge
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D018482:Muscle, Skeletal / Q000503:physiopathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D016328:NF-kappa B / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D051996:Transcription Factor RelA / Q000235:genetics
chemical_list: D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse