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

Abstract

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

Paradoxical effect of IKKβ inhibition on the expression of E3 ubiquitin ligases and unloading-induced skeletal muscle atrophy

“…These data correlate well with previously published data on decreased I κ B α content in mice during 3‐ and 7‐day unloading (Judge et al. 2007). We showed that pharmacological inhibition of IKKβ activity using IMD‐0354 during unloading blocked I κ B α degradation.…”

“…A similar decrease in the I κ B α level of expression was reported previously after 3 and 7 days of unloading in the rat model (Judge et al. 2007). Mice with muscle‐specific transgenic expression of activated IKK β have profound muscle wasting due to the activation of NF‐ κ B/MuRF (Cai et al.…”

“…I κ B α expression vector that was used in these experiments represents N‐terminus truncated version of I κ B α that has strong inhibiting activity on the components of NF‐ κ B pathway (Judge et al. 2007). …”

“…2002; Judge et al. 2007). We hypothesize that IKK β and IkB α regulation of NF‐ κ B activity and muscle atrophy during unloading is more complex and multifaceted than merely a simple decrease in the I κ B α content and it requires further studies.…”

“…2014) and IκB α level was decreased (Judge et al. 2007). In this study, we for the first time tested the ability of IMD‐0354 to block I κ B α phosphorylation/degradation in vivo during muscle unloading.…”