Although crucial roles for nuclear factor kappaB (NF-kB) signaling have been identified in diverse cell types, a role for NF-kB mediated transcription in skeletal muscle atrophy is just beginning to be revealed. 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-kB activity is induced in muscle atrophy due to unloading, and genetic evidence has shown important roles for Bcl3 (a NF-kB transcriptional co-activator), Nfkb1 (encodes p50), and the inhibitor of kB alpha (IkBa) in unloading atrophy. The upstream kinase (IKKb) of IkBa is therefore also likely involved. The most abundant Rel proteins that bind IkBa in muscle are p65 and p50, and while p50 is required for atrophy, a role for p65 is equivocal. The long term goal of this work is to identify further, the proteins in IKK-lkB-NF-kB signaling that are necessary and sufficient for muscle disuse atrophy and to identify direct NF-kB target genes.
The Specific Aims are to: 1) further elucidate the roles of p50 and Bcl-3 in disuse atrophy;2) determine if p65 is necessary or sufficient for disuse atrophy;3) test if IKKb, IKKa, and IKKg are required for disuse atrophy;4) determine if selected genes that are upregulated in unloaded muscle are bona fide NF-kB target genes. To achieve these aims, plasmids encoding dominant negative forms of the genes involved in IKK-lkB-NF-kB signaling will be injected into rodent skeletal muscle to determine if normal markers of unloading atrophy are blocked (NF-kB activation, increased ubiquitin conjugates, decreased fiber area, and atrophy gene expression). To test if a protein is sufficient for atrophy, wild type forms of proteins will be overexpressed. Concurrent with the identification of the NF-kB signaling proteins involved will be the discovery of NF-kB target genes by using in vivo promoter analysis. 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. This work will identify proteins required for the progression of muscle atrophy.
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