NF-kappaB functions in stromal fibroblasts to regulate early postnatal muscle development.
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.
Dahlman
Jason M
JM
Department of Molecular Virology, Immunology, and Medical Genetics, Human Cancer Genetics Program, Ohio State University, Columbus, Ohio 43210, USA.
Bakkar
Nadine
N
He
Wei
W
Guttridge
Denis C
DC
D000818:Animals; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D024510:Muscle Development / Q000502:physiology*; D018482:Muscle, Skeletal / Q000254:growth & development* / Q000378:metabolism; D032448:Myoblasts, Skeletal / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*
D020672:I-kappa B Proteins; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D051550:I-kappa B Kinase