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