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.
|Wu, Chia-Ling; Cornwell, Evangeline W; Jackman, Robert W et al. (2014) NF-?B but not FoxO sites in the MuRF1 promoter are required for transcriptional activation in disuse muscle atrophy. Am J Physiol Cell Physiol 306:C762-7|
|Jackman, Robert W; Cornwell, Evangeline W; Wu, Chia-Ling et al. (2013) Nuclear factor-?B signalling and transcriptional regulation in skeletal muscle atrophy. Exp Physiol 98:19-24|
|Yamaki, Takuo; Wu, Chia-Ling; Gustin, Michael et al. (2012) Rel A/p65 is required for cytokine-induced myotube atrophy. Am J Physiol Cell Physiol 303:C135-42|
|Wu, Chia-Ling; Kandarian, Susan C (2012) Protein overexpression in skeletal muscle using plasmid-based gene transfer to elucidate mechanisms controlling fiber size. Methods Mol Biol 798:231-43|
|Jackman, Robert W; Wu, Chia-Ling; Kandarian, Susan C (2012) The ChIP-seq-defined networks of Bcl-3 gene binding support its required role in skeletal muscle atrophy. PLoS One 7:e51478|
|Wu, Chia-Ling; Kandarian, Susan C; Jackman, Robert W (2011) Identification of genes that elicit disuse muscle atrophy via the transcription factors p50 and Bcl-3. PLoS One 6:e16171|
|Reed, S A; Senf, S M; Cornwell, E W et al. (2011) Inhibition of IkappaB kinase alpha (IKK?) or IKKbeta (IKK?) plus forkhead box O (Foxo) abolishes skeletal muscle atrophy. Biochem Biophys Res Commun 405:491-6|
|Van Gammeren, Darin; Damrauer, Jeffrey S; Jackman, Robert W et al. (2009) The IkappaB kinases IKKalpha and IKKbeta are necessary and sufficient for skeletal muscle atrophy. FASEB J 23:362-70|
|Jackman, Robert W; Rhoads, Mary G; Cornwell, Evangeline et al. (2009) Microtubule-mediated NF-kappaB activation in the TNF-alpha signaling pathway. Exp Cell Res 315:3242-9|
|Koncarevic, Alan; Jackman, Robert W; Kandarian, Susan C (2007) The ubiquitin-protein ligase Nedd4 targets Notch1 in skeletal muscle and distinguishes the subset of atrophies caused by reduced muscle tension. FASEB J 21:427-37|
Showing the most recent 10 out of 14 publications