making muscle wasting history

The ikappaB kinase(IKKalpha, beta and the regulatory subunit IKKgamma) complex regulates nuclear factor of kappaB (NF-kappaB) transcriptional activity, which is unregulated in many chronic inflammatory diseases. NF-kappaB signalling promotes inflammation and limits muscle regeneration in duchenne muscular dystrophy (DMD), resulting in fibrotic and fatty tissue replacement of muscle that exacerbates the wasting process in dystrophic muscles. Here, we examined whether dominant-negative forms of IKKalpha (IKKalpha-dn) and IKKbeta-dn) delivered by adeno-associated viral(AAV) vectors to the gastrocnemius(GAS) and tibialis anterior(TA) muscles of 1, 2 and 11-month-old mdx mice, a murine DMD model, block NF-kappaB activation and increase muscle regeneration. At 1 month post-treatment, the levels of nuclear NF-kappaB in locally treated muscle were decreased by gene transfer with either AAV-CMV-IKKalpha-AAV-CMV-IKKbeta-dn, but not by IKK wild-type controls (IKKalpha and beta) or phosphate-buffered saline (PBS). Although treatment with AAV-IKKalpha-dn or AAV-IKKalphaor AAV-IKKbeta-dn vectors had no significant effect on muscle regeneration in young mdx mice treated 1 and 2 month of age and collected 1 month later, treatment of old (11 months) with AAV-CMV-IKKalpha-dn or AAV-CMV-IKKbeta-dn significantly increased levels of muscle regeneration. In addition, there was a significant decrease in myofiber necrosis in the AAV-IKKalpha-dn and AAV-IKKbeta-dn treated mdx muscle in both young and old mice. These results demonstrate that inhibition of IKKalpha or IKKbeta in dystrophic muscle reduces the adverse effects of NF-kappaB signaling, resulting in a therapeutic effect. Moreover, these results clearly demonstrate the therapeutic benefits of inhibiting NF-kappaB activation by AAV gene transfer in dystrophic muscle to promote regeneration, particularly in older mdx mice, and block necrosis. Gene therapy advance online publication, 19 August 2010