title: IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis.
abstract: 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.
authors.affiliation: Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Bakkar
authors.forename: Jingxin
authors.initials: J
authors.lastname: Wang
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Ladner
authors.forename: Huating
authors.initials: H
authors.lastname: Wang
authors.forename: Jason M
authors.initials: JM
authors.lastname: Dahlman
authors.forename: Micheal
authors.initials: M
authors.lastname: Carathers
authors.forename: Swarnali
authors.initials: S
authors.lastname: Acharyya
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hollenbach
authors.forename: Denis C
authors.initials: DC
authors.lastname: Guttridge
mesh_terms: 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
chemical_list: 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