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Authordc.contributor.authorHenríquez Olguín, Carlos
Authordc.contributor.authorAltamirano, Francisco
Authordc.contributor.authorValladares, Denisse
Authordc.contributor.authorLópez, José R.
Authordc.contributor.authorAllen, Paul D.
Authordc.contributor.authorJaimovich Pérez, Enrique
Admission datedc.date.accessioned2019-03-15T16:09:10Z
Available datedc.date.available2019-03-15T16:09:10Z
Publication datedc.date.issued2015
Cita de ítemdc.identifier.citationBiochimica et Biophysica Acta 1852 (2015) 1410–1419
Identifierdc.identifier.issn1879260X
Identifierdc.identifier.issn09254439
Identifierdc.identifier.other10.1016/j.bbadis.2015.03.012
Identifierdc.identifier.urihttps://repositorio.uchile.cl/handle/2250/166433
Abstractdc.description.abstractDuchenne 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-κB activation and interleukin6 (IL-6) expression induced by membrane depolarization in dystrophic mdx myotubes. Membrane depolarization elicited by electrical stimulation increased p65 phosphorylation, NF-κB transcriptional activity and NF-κB-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-κB 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-κB activation we found that in wt myotubes external administration of 50 μM H2O2 increased NF-κB activity; after administration of 100 and 200 μM H2O2 there was no effect. In mdx myotubes there was a dose-dependent reduction in NF-κB activity in response to external administration of H2O2, with a significant effect of 100 μM and 200 μM, suggesting that ROS levels are critical for NF-κB activity. Prior blockage with NOX2 inhibitors blunted the effects of electrical stimuli in both NF-κB activation and IL-6 expression. Finally, to ascertain whether stimulation of NF-κB and IL-6 gene expression by the inflammatory pathway is also impaired in mdx myotubes, we studied the effect of lipopolysaccharide on both NF-κB activation and IL-6 expression. Exposure to lipopolysaccharide induced a dramatic increase in both NF-κB 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-κB 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.
Lenguagedc.language.isoen
Publisherdc.publisherElsevier
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile
Link to Licensedc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/cl/
Sourcedc.sourceBiochimica et Biophysica Acta - Molecular Basis of Disease
Keywordsdc.subjectCalcium
Keywordsdc.subjectDuchenne muscular dystrophy
Keywordsdc.subjectInterleukin-6
Keywordsdc.subjectMembrane depolarization
Keywordsdc.subjectNF-κB
Keywordsdc.subjectReactive oxygen species
Títulodc.titleAltered ROS production, NF-κB activation and interleukin-6 gene expression induced by electrical stimulation in dystrophic mdx skeletal muscle cells
Document typedc.typeArtículo de revista
dcterms.accessRightsdcterms.accessRightsAcceso abierto
Catalogueruchile.catalogadorlaj
Indexationuchile.indexArtículo de publicación SCOPUS
uchile.cosechauchile.cosechaSI


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Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile