Interplay of IKK/NF-kappaB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy.
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.
Acharyya
Swarnali
S
Human Cancer Genetics Program and Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Villalta
S Armando
SA
Bakkar
Nadine
N
Bupha-Intr
Tepmanas
T
Janssen
Paul M L
PM
Carathers
Micheal
M
Li
Zhi-Wei
ZW
Beg
Amer A
AA
Ghosh
Sankar
S
Sahenk
Zarife
Z
Weinstein
Michael
M
Gardner
Katherine L
KL
Rafael-Fortney
Jill A
JA
Karin
Michael
M
Tidball
James G
JG
Baldwin
Albert S
AS
Guttridge
Denis C
DC
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
D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse