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Molecular Mechanisms of NF-kB Regulation of Skeletal Myogenesis

Bakkar, Nadine
http://rave.ohiolink.edu/etdc/view?acc_num=osu1218029902

Abstract Details

2008, Doctor of Philosophy, Ohio State University, Molecular, Cellular, and Developmental Biology.
NF-kB is a ubiquitous transcription factor involved in the regulation of innate immunity, cellular survival, proliferation, as well as differentiation. Its deregulation is associated with various diseases, and have thus been the target of developing therapeutic strategies. Skeletal muscle diseases are one field where this transcription factor is receiving recent attention, owing to its implication in muscular dystrophy, wasting and regeneration. In this dissertation, we focused on NF-kB regulation of myogenic differentiation, in an attempt to further understand the complex ways this transcription factor follows to regulate muscle development and extrapolate it to disease.In chapter 2, we focused on Myostatin (Mstn) a potent negative regulator of myogenesis that can inhibit myoblast proliferation and suppress synthesis of MyoD. NF-kB is similarly able to promote myoblast growth and induce loss of MyoD message. Given the similarities of these phenotypes, we examined potential Mstn and NF-kB signaling crosstalks in myoblasts and differentiated myotubes. Results show that Mstn does not activate NF-kB, nor does activated NF-kB induce Mstn expression. Furthermore, Mstn inhibition of differentiation can still occur in cells devoid of NF-kB activity. Such findings were confirmed in proliferating muscle precursors as well as mature muscle fibers and thus highlight the intrinsic differences between those two signaling pathways in the regulation of skeletal myogenesis, In chapter 3, we examined NF-kB regulation of skeletal myogenesis using genetic knockout models. Previous studies had attempted to investigate such a regulation, yet results remained perplexing, with both pro- and anti-myogenic roles of NF-kB documented. Using primary myoblasts and muscles devoid of NF-kB classical pathway components p65 or IKKb, we show that this canonical signaling is a negative regulator of myogenesis and gets downregulated during differentiation. On the other hand, NF-kB alternative signaling, mediated by IKKa activating the RelB/p52 complex is turned on and regulates mitochondrial biogenesis. Such a pathway is hence involved in the energy production and subsequent maintenance of newly formed myotubes. Consequently, our findings help to resolve the conundrum of NF-kB signaling in myogenesis by showing the existence of two opposing NF-kB pathways that function at temporally distinct stages of differentiation: classical signals inhibit premature myogenesis while alternative pathway activation regulate energy production and maintenance of nascent myofibers. Collectively, results presented in this dissertation highlight the various branches through which NF-kB signals to regulate skeletal myogenesis, emphasizing the need to take this complex regulation into account in clinical strategies aimed to modulate its activity.
Denis Guttridge, PhD (Advisor)
Jill Rafael-Fortney, PhD (Committee Member)
Gustavo Leone, PhD (Committee Member)
Michael Ostrowski, PhD (Committee Member)
113 p.
Molecular Biology

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Citations

  • Bakkar, N. (2008). Molecular Mechanisms of NF-kB Regulation of Skeletal Myogenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1218029902

    APA Style (7th edition)

  • Bakkar, Nadine. Molecular Mechanisms of NF-kB Regulation of Skeletal Myogenesis. 2008. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1218029902.

    MLA Style (8th edition)

  • Bakkar, Nadine. "Molecular Mechanisms of NF-kB Regulation of Skeletal Myogenesis." Doctoral dissertation, Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1218029902

    Chicago Manual of Style (17th edition)

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© 2008, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.