TWEAK and cIAP1 regulate myoblast fusion through the noncanonical NF-κB signaling pathway.
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 κB (NF-κB) 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-κB pathway and an increase in the number of nuclei per myotube. Knockdown of essential mediators of NF-κB signaling, such as p100, RelB, inhibitor of κB kinase α, and NF-κB-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-κB 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-κB pathway, also increased myoblast fusion, without causing atrophy or impairing myogenesis. These results identify roles for TWEAK, cIAP1, and noncanonical NF-κB signaling in the regulation of myoblast fusion and highlight a role for cytokine signaling during adult skeletal myogenesis.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Emeka K
EK
Enwere
Janelle
J
Holbrook
Rim
R
Lejmi-Mrad
Jennifer
J
Vineham
Kristen
K
Timusk
Baktharaman
B
Sivaraj
Methvin
M
Isaac
David
D
Uehling
Rima
R
Al-awar
Eric
E
LaCasse
Robert G
RG
Korneluk
D000818:Animals; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002460:Cell Line; D000074049:Cytokine TWEAK; D005786:Gene Expression Regulation; D005838:Genotype; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D009132:Muscles / Q000378:metabolism; D032446:Myoblasts / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000502:physiology*
D000074049:Cytokine TWEAK; D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D034741:RNA, Small Interfering; C491645:Tnfsf12 protein, mouse; D048069:Tumor Necrosis Factors; D001973:Bromodeoxyuridine