期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 292, 期 1, 页码 C372-C382出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00293.2006
关键词
disuse; nuclear factor-kappa B signaling; unloading; muscle wasting; ubiquitination; atrophy genes; inhibitory factor kappa B alpha
资金
- NIAMS NIH HHS [AR 41705] Funding Source: Medline
- NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES [R29AR041705, R01AR041705] Funding Source: NIH RePORTER
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.
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