Title

NF-kappaB functions in stromal fibroblasts to regulate early postnatal muscle development

Document Type

Article

Abstract

Classical NF-kappaB activity functions as an inhibitor of the skeletal muscle myogenic program. Recent findings reveal that even in newborn RelA/p65(-/-) mice, myofiber numbers are increased over that of wild type mice, suggesting that NF-kappaB may be a contributing factor in early postnatal skeletal muscle development. Here we show that in addition to p65 deficiency, repression of NF-kappaB with the IkappaB alpha-SR transdominant inhibitor or with muscle-specific deletion of IKKbeta resulted in similar increases in total fiber numbers as well as an up-regulation of myogenic gene products. Upon further characterization of early postnatal muscle, we observed that NF-kappaB activity progressively declines within the first few weeks of development. At birth, the majority of this activity is compartmentalized to muscle fibers, but by neonatal day 8 NF-kappaB activity from the myofibers diminishes, and instead, stromal fibroblasts become the main cellular compartment within the muscle that contains active NF-kappaB. We find that NF-kappaB functions in these fibroblasts to regulate inducible nitric-oxide synthase expression, which we show is important for myoblast fusion during the growth and maturation process of skeletal muscle. Together, these data broaden our understanding of NF-kappaB during development by showing that in addition to its role as a negative regulator of myogenesis, NF-kappaB also regulates nitric-oxide synthase expression within stromal fibroblasts to stimulate myoblast fusion and muscle hypertrophy.

Medical Subject Headings

Animals; Fibroblasts (metabolism); Gene Expression Regulation, Enzymologic (physiology); I-kappa B Kinase (genetics, metabolism); I-kappa B Proteins (genetics, metabolism); Mice; Mice, Knockout; Muscle Development (physiology); Muscle, Skeletal (growth & development, metabolism); Myoblasts, Skeletal (metabolism); Nitric Oxide Synthase Type II (biosynthesis, genetics); Transcription Factor RelA (genetics, metabolism)

Publication Date

2-19-2010

Publication Title

The Journal of biological chemistry

E-ISSN

1083-351X

Volume

285

Issue

8

First Page

5479

Last Page

87

PubMed ID

20018862

Digital Object Identifier (DOI)

10.1074/jbc.M109.075606

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