Interplay of IKK/NF-κB 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 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.

MicroRNA-431 accelerates muscle regeneration and ameliorates muscular dystrophy by targeting Pax7 in mice

“…Although this disease is caused primarily by a mutation in the gene encoding dystrophin 46 , several genes slow disease progression in mdx mice [47][48][49][50] . Thus, therapeutic strategies may not be limited to those directly targeting the dystrophin gene.…”

AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice

“…Recently, blocking IKKb has been considered as a potential approach for anti-chronic inflammation in dystrophic muscles by targeting the upstream activator of the classical NF-kB pathway. The peptide inhibitor of IKKb, 9 for example, reduced inflammation and necrosis while enhancing regeneration. However, these approaches require repeated treatments and have the potential for systemic side effects.…”

“…9,32 Hence, we attempted to silence the p65 gene to improve the pathologies observed in mdx mice. Our findings indicate that AAV-based p65-shRNA has the capacity to decrease immune cell infiltration, to inhibit necrosis and to protect the myofiber membranes.…”

“…8 Chronic inflammation has a key role in the progressive muscle wasting and degeneration observed in DMD patients. 9 Previous studies demonstrate that in muscular dystrophies, chronic inflammation is promoted by an upregulated NF-kB signaling pathway. 10,11 Elevated levels of NF-kB activation have been detected in more than one type of muscular dystrophy, including DMD 12 and limb girdle muscular dystrophy.…”

“…9 AAV vectors have the advantageous biological property of being capable of infecting a wide range of host cell types including muscle, which makes AAV a particularly good vector for muscle-directed gene therapy, 14 --16 especially for muscular dystrophies. 17 In AAV vector-based mini-dystrophin gene replacement treatment of dystrophin-deficient (dysÀ/À) (mdx) or dystrophin/utrophin double knock-out (dysÀ/À:utrÀ/À) mice 17 --19 and canine models, 20 as well as in human clinical trials for DMD, 21 the AAV vector delivery system thus far represents one of the most promising approaches to aid in the treatment of DMD.…”