ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers

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dc.contributor.authorGonzalez, D.
dc.contributor.authorContreras, O.
dc.contributor.authorRebolledo, D.L.
dc.contributor.authorEspinoza, J.P.
dc.contributor.authorVan Zundert, B.
dc.contributor.authorBrandan, E.
dc.date.accessioned2017-11-24T14:06:31Z
dc.date.available2017-11-24T14:06:31Z
dc.date.issued2017-05
dc.descriptionIndexación: Web of Science; Scopus.es_CL
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which upper and lower motoneurons degenerate leading to muscle wasting, paralysis and eventually death from respiratory failure. Several studies indicate that skeletal muscle contributes to disease progression; however the molecular mechanisms remain elusive. Fibrosis is a common feature in skeletal muscle under chronic damage conditions such as those caused by muscular dystrophies or denervation. However, the exact mechanisms of fibrosis induction and the cellular bases of this pathological response are unknown. We show that extracellular matrix (ECM) components are augmented in skeletal muscles of symptomatic hSOD1G93A mice, a widely used murine model of ALS. These mice also show increased TGF-β1 mRNA levels, total Smad3 protein levels and p-Smad3 positive nuclei. Furthermore, platelet-derived growth factor receptor-α (PDGFRα), Tcf4 and α-smooth muscle actin (α-SMA) levels are augmented in the skeletal muscle of symptomatic hSOD1G93A mice. Additionally, the fibro/adipogenic progenitors (FAPs), which are the main producers of ECM constituents, are also increased in these pathogenic conditions. Therefore, FAPs and ECM components are more abundant in symptomatic stages of the disease than in pre-symptomatic stages. We present evidence that fibrosis observed in skeletal muscle of symptomatic hSOD1G93A mice is accompanied with an induction of TGF-β signaling, and also that FAPs might be involved in triggering a fibrotic response. Co-localization of p-Smad3 positive cells together with PDGFRα was observed in the interstitial cells of skeletal muscles from symptomatic hSOD1G93A mice. Finally, the targeting of pro-fibrotic factors such as TGF-β, CTGF/CCN2 and platelet-derived growth factor (PDGF) signaling pathway might be a suitable therapeutic approach to improve muscle function in several degenerative diseases. © 2017 Gonzalez et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.es_CL
dc.description.urihttp://journals.plos.org/plosone/article?id=10.1371/journal.pone.0177649
dc.identifier.citationPLoS ONE. Volume 12, Issue 5, May 2017, Article number e0177649es_CL
dc.identifier.issn1932-6203
dc.identifier.otherDOI: 10.1371/journal.pone.0177649
dc.identifier.urihttp://repositorio.unab.cl/xmlui/handle/ria/4721
dc.language.isoenes_CL
dc.publisherPublic Library of Sciencees_CL
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAdipogenesises_CL
dc.subjectAmyotrophic Lateral Sclerosises_CL
dc.subjectAnimalses_CL
dc.subjectAtrophyes_CL
dc.subjectBiomarkerses_CL
dc.subjectExtracellular Matrixes_CL
dc.subjectFibrosises_CL
dc.subjectHumanses_CL
dc.subjectMalees_CL
dc.subjectMicees_CL
dc.subjectMice, Transgenices_CL
dc.subjectSkeletales_CL
dc.subjectPhenotypees_CL
dc.subjectSignal Transductiones_CL
dc.subjectStem Cellses_CL
dc.subjectSuperoxide Dismutase-1es_CL
dc.subjectTransforming Growthes_CL
dc.subjectFactor betaes_CL
dc.titleALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markerses_CL
dc.typeArtículoes_CL
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