The NF-kappaB (NF-kB) transcription factor and its upstream regulator, the 1-kappaB kinase (IKK), represent a major signaling pathway involved in the regulation of cell growth, differentiation and cellular survival. This pathway is often found deregulated in diseases associated with chronic inflammation such as arthritis, inflammatory bowel disease and cancer. Accumulating evidence suggest that NF-kB also functions in skeletal muscle disorders but its involvement and mechanisms of action are not well defined. Insight into how NF-kB/IKK participate in muscle disease may be gained by understanding on a more basic level how this signaling pathway functions in skeletal myogenesis. Several studies have been performed to look at this property of NF-kB, but results have been inconsistent as to whether this transcription factor functions as a promoter or inhibitor of myogenesis. Potentially contributing to this confusion is the recent discovery that NF-kB/IKK signaling is composed of not one, but two signaling pathways referred to as the classical and alternative pathways. These pathways signal through different NF-kB dimer subunits thought to regulate a distinct set of genes. To better define the role of NF-kB/IKK signaling in myogenesis we utilized a genetic approach with knockouts of the NF-kB family and IKK complex. Based on preliminary data, we hypothesize that the classical and alternative NF-kB/IKK pathways function in distinct manners to regulate skeletal muscle cell differentiation. While the classical pathway functions through IKK beta and the RelA (p65) subunit to repress differentiation in proliferating myoblasts, activation of the alternative pathway via IKK alpha and the p52/RelB complex functions in the termination or maintenance of differentiated myotubes. To test this hypothesis we propose to perform the following three aims: 1) establish the function of the classical pathway in a primary myogenic culture system; 2) determine whether regulation of myogenesis by IKK beta and p65 is relevant in vivo; and 3) determine the regulation and function of IKK alpha and the alternative pathway in skeletal muscle differentiation. Completion of these aims should not only advance our understanding of NFkB/IKK function in skeletal myogenesis, but it should also provide insight in how these signaling pathways participate in the onset or progression of skeletal muscle disorders. ? ? ? ?
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