Regulation of Gene Expression in Skeletal Muscle: NF-kB Signaling in Atrophy

Boston University (Charles River Campus), Boston MA

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Abstract

DESCRIPTION (provided by applicant): 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[unreadable]) 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[unreadable] 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. PUBLIC HEALTH RELEVANCE: 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.