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MUSCLE CELL BIOLOGY AND CELL MOTILITY

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

¹Department of Health Sciences, Boston University, Boston; ²Genzyme, Waltham, Massachusetts; and ³Division of Immunology, Department of Medicine, Weill School of Medicine, Cornell University, New York, New York

Submitted 26 May 2006 ; accepted in final form 11 August 2006

Skeletal muscle atrophy is associated with a marked and sustained activation of nuclear factor-B (NF-B) activity. Previous work showed that p50 is one of the NF-B family members required for this activation and for muscle atrophy. In this work, we tested whether another NF-B family member, c-Rel, is required for atrophy. Because endogenous inhibitory factor B (IB) was activated (i.e., decreased) at 3 and 7 days of muscle disuse (i.e., hindlimb unloading), we also tested if IB, 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 IB (IBN) in soleus muscles, which were either unloaded or weight bearing. IBN expression abolished the unloading-induced increase in both NF-B activation and total ubiquitinated protein. IBN inhibited unloading-induced fiber atrophy by 40%. The expression of certain genes known to be upregulated with atrophy were significantly inhibited by IBN expression during unloading, including MAFbx/atrogin-1, Nedd4, IEX, 4E-BP1, FOXO3a, and cathepsin L, suggesting these genes may be targets of NF-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 IB degradation is required for the unloading-induced decrease in fiber size, the increase in protein ubiquitination, activation of NF-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-B/IB family members in skeletal muscle atrophy, and they provide new candidate NF-B target genes for further study.

disuse; nuclear factor-B signaling; unloading; muscle wasting; ubiquitination; atrophy genes; inhibitory factor B

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