Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 287, Issue 25, Pages 20876-20887Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M112.344929
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Funding
- National Institutes of Health [AR43140, AR052354]
- Fondo Nacional de Investigacion Cientifica y Tecnologica [1110467]
- Fondo de Financiamiento de Centros de Excelencia en Investigacion [15010006]
- Asotiation Francaise Contre les Myopathies [14562]
- Comision Nacional de Investigacion Cientifica y Tecnologica [AT-24100066]
- Vicerrectoria de Asuntos Academicos
- Universidad de Chile
- Programa de Mejoramiento de lo Calidad y Equidad de la Educacion [UCH 0714]
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Duchenne muscular dystrophy (DMD) is a genetic disorder caused by dystrophin mutations, characterized by chronic inflammation and severe muscle wasting. Dystrophic muscles exhibit activated immune cell infiltrates, up-regulated inflammatory gene expression, and increased NF-kappa B activity, but the contribution of the skeletal muscle cell to this process has been unclear. The aim of this work was to study the pathways that contribute to the increased resting calcium ([Ca2+](rest)) observed in mdx myotubes and its possible link with up-regulation of NF-kappa B and pro-inflammatory gene expression in dystrophic muscle cells. [Ca2+](rest) was higher in mdx than in WT myotubes (308 +/- 6 versus 113 +/- 2 nM, p < 0.001). In mdx myotubes, both the inhibition of Ca2+ entry (low Ca2+ solution, Ca2+-free solution, and Gd3+) and blockade of either ryanodine receptors or inositol 1,4,5-trisphosphate receptors reduced [Ca2+](rest). Basal activity of NF-kappa B was significantly up-regulated in mdx versus WT myotubes. There was an increased transcriptional activity and p65 nuclear localization, which could be reversed when [Ca2+](rest) was reduced. Levels of mRNA for TNF alpha, IL-1 beta, and IL-6 were similar in WT and mdx myotubes, whereas inducible nitric-oxide synthase (iNOS) expression was increased 5-fold. Reducing [Ca2+](rest) using different strategies reduced iNOS gene expression presumably as a result of decreased activation of NF-kappa B. We propose that NF-kappa B, modulated by increased [Ca2+](rest), is constitutively active in mdx myotubes, and this mechanism can account for iNOS overexpression and the increase in reactive nitrogen species that promote damage in dystrophic skeletal muscle cells.
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