Diverse functions for nuclear factor kappaB (NF-?B) signaling have been established in a variety of cell types, but we are just beginning to identify a role in skeletal muscle (fiber) atrophy. The identification of a signaling pathway required for disuse atrophy, and of the genes targeted by this pathway have significant clinical implications for ameliorating muscle atrophy. NF-?B activity is induced in muscle atrophy due to unloading, and genetic evidence has shown crucial roles for Bcl-3 (a NF-?B transcriptional co-activator), Nfkb1 (encodes p50), and the inhibitor of ?B alpha (?Ba) in unloading atrophy. The upstream kinases (IKKa and IKK?) of I?Ba are also likely involved. The most abundant Rel proteins that bind I?Ba in muscle are p65 and p50, and while p50 is required for atrophy, a role for p65 is equivocal. The central hypothesis of this work is that specific components of NF-?B signaling, including the target genes activated by specific NF-?B transcription complexes, are an integral mechanism of muscle atrophy due to disuse.
The Specific Aims are to: (1) identify if p50 and Bcl-3 are sufficient to induce atrophy;(2) determine if p65 is necessary or sufficient for disuse atrophy;(3) determine if the upstream NF-?B kinases (i.e., I?B kinases), IKK? and IKKa are necessary or sufficient for disuse atrophy, alone or in combination;(4) Discover NF-?B target genes in 7-day unloaded muscles using genome-wide microarray expression analysis in conjunction with in vivo genome-wide NF-?B transcription factor binding using ChIP-on-chip analysis.
Aim 4 is the focus of this """"""""revision"""""""" application because it is a significant expansion of the original approach to identify NF-?B target genes during muscle atrophy. Importantly, in the revised Aim 4 we will discover the NF-?B target genes that direct the muscle atrophy process using an unbiased genome-wide approach. This knowledge will allow for the development of rational pharmaceutical targets for the amelioration of atrophy.
This work will identify key proteins required for the progression of muscle atrophy. Understanding the molecular underpinnings of muscle atrophy due to inactivity is essential to develop rational pharmacological and/or nutritional compounds that can be used to attenuate muscle fatigue and loss of muscle strength that are symptoms of muscle atrophy.
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