| First Author | Henríquez-Olguín C | Year | 2015 |
| Journal | Biochim Biophys Acta | Volume | 1852 |
| Issue | 7 | Pages | 1410-9 |
| PubMed ID | 25857619 | Mgi Jnum | J:230541 |
| Mgi Id | MGI:5762764 | Doi | 10.1016/j.bbadis.2015.03.012 |
| Citation | Henriquez-Olguin C, et al. (2015) Altered ROS production, NF-kappaB activation and interleukin-6 gene expression induced by electrical stimulation in dystrophic mdx skeletal muscle cells. Biochim Biophys Acta 1852(7):1410-9 |
| abstractText | Duchenne muscular dystrophy is a fatal X-linked genetic disease, caused by mutations in the dystrophin gene, which cause functional loss of this protein. This pathology is associated with an increased production of reactive oxygen (ROS) and nitrogen species. The aim of this work was to study the alterations in NF-kappaB activation and interleukin-6 (IL-6) expression induced by membrane depolarization in dystrophic mdx myotubes. Membrane depolarization elicited by electrical stimulation increased p65 phosphorylation, NF-kappaB transcriptional activity and NF-kappaB-dependent IL-6 expression in wt myotubes, whereas in mdx myotubes it had the opposite effect. We have previously shown that depolarization-induced intracellular Ca2+ increases and ROS production are necessary for NF-kappaB activation and stimulation of gene expression in wt myotubes. Dystrophic myotubes showed a reduced amplitude and area under the curve of the Ca2+ transient elicited by electrical stimulation. On the other hand, electrical stimuli induced higher ROS production in mdx than wt myotubes, which were blocked by NOX2 inhibitors. Moreover, mRNA expression and protein levels of the NADPH oxidase subunits: p47phox and gp91phox were increased in mdx myotubes. Looking at ROS-dependence of NF-kappaB activation we found that in wt myotubes external administration of 50 muM H2O2 increased NF-kappaB activity; after administration of 100 and 200 muM H2O2 there was no effect. In mdx myotubes there was a dose-dependent reduction in NF-kappaB activity in response to external administration of H2O2, with a significant effect of 100 muM and 200 muM, suggesting that ROS levels are critical for NF-kappaB activity. Prior blockage with NOX2 inhibitors blunted the effects of electrical stimuli in both NF-kappaB activation and IL-6 expression. Finally, to ascertain whether stimulation of NF-kappaB and IL-6 gene expression by the inflammatory pathway is also impaired in mdx myotubes, we studied the effect of lipopolysaccharide on both NF-kappaB activation and IL-6 expression. Exposure to lipopolysaccharide induced a dramatic increase in both NF-kappaB activation and IL-6 expression in both wt and mdx myotubes, suggesting that the altered IL-6 gene expression after electrical stimulation in mdx muscle cells is due to dysregulation of Ca2+ release and ROS production, both of which impinge on NF-kappaB signaling. IL-6 is a key metabolic modulator that is released by the skeletal muscle to coordinate a multi-systemic response (liver, muscle, and adipocytes) during physical exercise; the alteration of this response in dystrophic muscles may contribute to an abnormal response to contraction and exercise. |
