IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis.
Nuclear factor kappaB (NF-kappaB) is involved in multiple skeletal muscle disorders, but how it functions in differentiation remains elusive given that both anti- and promyogenic activities have been described. In this study, we resolve this by showing that myogenesis is controlled by opposing NF-kappaB signaling pathways. We find that myogenesis is enhanced in MyoD-expressing fibroblasts deficient in classical pathway components RelA/p65, inhibitor of kappaB kinase beta (IKKbeta), or IKKgamma. Similar increases occur in myoblasts lacking RelA/p65 or IKKbeta, and muscles from RelA/p65 or IKKbeta mutant mice also contain higher fiber numbers. Moreover, we show that during differentiation, classical NF-kappaB signaling decreases, whereas the induction of alternative members IKKalpha, RelB, and p52 occurs late in myogenesis. Myotube formation does not require alternative signaling, but it is important for myotube maintenance in response to metabolic stress. Furthermore, overexpression or knockdown of IKKalpha regulates mitochondrial content and function, suggesting that alternative signaling stimulates mitochondrial biogenesis. Together, these data reveal a unique IKK/NF-kappaB signaling switch that functions to both inhibit differentiation and promote myotube homeostasis.
Bakkar
Nadine
N
Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
Wang
Jingxin
J
Ladner
Katherine J
KJ
Wang
Huating
H
Dahlman
Jason M
JM
Carathers
Micheal
M
Acharyya
Swarnali
S
Rudnicki
Michael A
MA
Hollenbach
Andrew D
AD
Guttridge
Denis C
DC
D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D024510:Muscle Development / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism* / Q000648:ultrastructure; D032448:Myoblasts, Skeletal / Q000378:metabolism* / Q000648:ultrastructure; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
D016328:NF-kappa B; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse