Role for IκBα, but not c-Rel, in skeletal muscle atrophy

Skeletal muscle atrophy is associated with a marked and sustained activation of nuclear factor-kappa B (NF-kappa B) activity. Previous work showed that p50 is one of the NF-kappa B family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-kappa B family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor kappa B alpha (I kappa B alpha) was activated (i.e., decreased) at 3 and 7 days of muscle disuse ( i.e., hindlimb unloading), we also tested if I kappa B alpha, which binds and retains Rel proteins in the cytosol, is required for atrophy and intermediates of the atrophy process. To do this, we electrotransferred a dominant negative I kappa B alpha (I kappa B alpha Delta N) in soleus muscles, which were either unloaded or weight bearing. I kappa B alpha Delta N expression abolished the unloading-induced increase in both NF-kappa B activation and total ubiquitinated protein. I kappa B alpha Delta N inhibited unloading- induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by I kappa B alpha Delta N expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-kappa B transcription factors. In contrast, c-Rel was not required for atrophy because the unloading- induced markers of atrophy were the same in c-rel(-/-) and wild-type mice. Thus I kappa B alpha degradation is required for the unloading- induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-kappa B signaling, and the expression of specific atrophy genes, but c-Rel is not. These data represent a significant advance in our understanding of the role of NF-kappa B/I kappa B family members in skeletal muscle atrophy, and they provide new candidate NF-kappa B target genes for further study.