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

Judge AR, Koncarevic A, Hunter RB, Liou H-C, Jackman RW, Kandarian SC. Role for I B , but not c-Rel, in skeletal muscle atrophy. Am J Physiol Cell Physiol 292: C372–C382, 2007. First published August 23, 2006; doi:10.1152/ajpcell.00293.2006.—Skeletal muscle atrophy is associated with a marked and sustained activation of nuclear factorB (NFB) activity. Previous work showed that p50 is one of the NFB family members required for this activation and for muscle atrophy. In this work, we tested whether another NFB family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor B (I B ) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if I B , 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 B (I B N) in soleus muscles, which were either unloaded or weight bearing. I B N expression abolished the unloading-induced increase in both NFB activation and total ubiquitinated protein. I B N inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by I B N expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NFB 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 B degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NFB 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 NFB/I B family members in skeletal muscle atrophy, and they provide new candidate NFB target genes for further study.