Title

IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis

Document Type

Article

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.

Medical Subject Headings

Animals; Animals, Newborn; Cell Differentiation (genetics); Cell Line; Cells, Cultured; Down-Regulation (genetics); Gene Expression Regulation, Developmental (genetics); I-kappa B Kinase (genetics, metabolism); Mice; Mice, Transgenic; Mitochondria (metabolism, ultrastructure); Muscle Development (genetics); Muscle Fibers, Skeletal (metabolism); Muscle, Skeletal (embryology, metabolism, ultrastructure); Myoblasts, Skeletal (metabolism, ultrastructure); NF-kappa B (metabolism); Signal Transduction (genetics); Transcription Factor RelA (genetics, metabolism)

Publication Date

2-25-2008

Publication Title

The Journal of cell biology

E-ISSN

1540-8140

Volume

180

Issue

4

First Page

787

Last Page

802

PubMed ID

18299349

Digital Object Identifier (DOI)

10.1083/jcb.200707179

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