Elucidation of NF-kB’s Involvement In Muscle Homeostasis

Mourkioti, F., Kratsios, P., Luedde, T., Song, Y.H., et al. J. Clin. Invest., 116, 2945-2954 (November, 2006).

The NF-kB signaling pathway has been implicated in certain aspects of muscle development and maintenance, including myogenic growth, differentiation, and muscle atrophy. However, in vivo studies have been limited by the lethality of NF-kB gene deletion in embryos. As a result, the present study focuses on the activating kinase inhibitor of NF-kB kinase 2 (IKK2) to examine the influence of this transcription factor in muscle homeostasis.

The loss of NF-kB signaling, created via the deletion of the gene for the muscle-specific IKK2 subunit of the IKK complex, resulted in an increase in intermediate fibers and an increase in titanic force under otherwise normal conditions. Moreover, denervation of such muscles had little effect on fiber size or on contractile force, in contrast with muscles from normal animals, which experience atrophy and lose strength after nerve transection. The beneficial effects of NF-kB depletion on muscle histology and physiology were traced to a promotion of protein synthesis and a down-regulation of protein degradation. IGF-1 supplementation, which has a similar effect on muscle metabolism, is additive with respect to the effect of IKK2 deletion on preventing muscle atrophy, suggesting that different mechanisms are involved. Finally, a separate study found that IKK2 deletion enhanced muscle regeneration following cardiotoxin administration at least partly by limiting the inflammatory response, as detected via histological examination.

The results of this study suggest that the NF-kB pathway is a suitable candidate for therapeutic intervention in the treatment of certain muscle disorders, particularly Duchenne muscular dystrophy, which has been associated with elevated NF-kB. It may also offer new opportunities to limit the muscle wasting that accompanies cardiac cachexia, cancer, and immune dysfunction.

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