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Sci. Signal., 16 October 2012
Vol. 5, Issue 246, p. ra75
[DOI: 10.1126/scisignal.2003086]

RESEARCH ARTICLES

TWEAK and cIAP1 Regulate Myoblast Fusion Through the Noncanonical NF-{kappa}B Signaling Pathway

Emeka K. Enwere1,2, Janelle Holbrook2, Rim Lejmi-Mrad2,3, Jennifer Vineham2,3, Kristen Timusk2,3, Baktharaman Sivaraj4, Methvin Isaac4, David Uehling4, Rima Al-awar4, Eric LaCasse2, and Robert G. Korneluk1,2,3*

1 Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
2 Apoptosis Research Centre, Children’s Hospital of Eastern Ontario, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.
3 Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
4 Medicinal Chemistry Platform, Ontario Institute for Cancer Research, 101 College Street, Toronto, Ontario M5G 0A3, Canada.

Abstract: The fusion of mononucleated muscle progenitor cells (myoblasts) into multinucleated muscle fibers is a critical aspect of muscle development and regeneration. We identified the noncanonical nuclear factor {kappa}B (NF-{kappa}B) pathway as a signaling axis that drives the recruitment of myoblasts into new muscle fibers. Loss of cellular inhibitor of apoptosis 1 (cIAP1) protein led to constitutive activation of the noncanonical NF-{kappa}B pathway and an increase in the number of nuclei per myotube. Knockdown of essential mediators of NF-{kappa}B signaling, such as p100, RelB, inhibitor of {kappa}B kinase α, and NF-{kappa}B–inducing kinase, attenuated myoblast fusion in wild-type myoblasts. In contrast, the extent of myoblast fusion was increased when the activity of the noncanonical NF-{kappa}B pathway was enhanced by increasing the abundance of p52 and RelB or decreasing the abundance of tumor necrosis factor (TNF) receptor–associated factor 3, an inhibitor of this pathway. Low concentrations of the cytokine TNF-like weak inducer of apoptosis (TWEAK), which preferentially activates the noncanonical NF-{kappa}B pathway, also increased myoblast fusion, without causing atrophy or impairing myogenesis. These results identify roles for TWEAK, cIAP1, and noncanonical NF-{kappa}B signaling in the regulation of myoblast fusion and highlight a role for cytokine signaling during adult skeletal myogenesis.

* To whom correspondence should be addressed. E-mail: bob{at}arc.cheo.ca

Citation: E. K. Enwere, J. Holbrook, R. Lejmi-Mrad, J. Vineham, K. Timusk, B. Sivaraj, M. Isaac, D. Uehling, R. Al-awar, E. LaCasse, R. G. Korneluk, TWEAK and cIAP1 Regulate Myoblast Fusion Through the Noncanonical NF-{kappa}B Signaling Pathway. Sci. Signal. 5, ra75 (2012).

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