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

David Gonzalez, Osvaldo Contreras, Daniela L. Rebolledo, Juan Pablo Espinoza, Brigitte Van Zundert, Enrique Brandan

Resultado de la investigación: Contribución a la publicaciónArticle

Resumen

Amyotrophic 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.

Idioma originalEnglish
Número de artículoe0177649
PublicaciónPLoS ONE
Volumen12
Número de edición5
Identificadores de objetos digitales
EstadoPublished - 1 may 2017

Huella dactilar

Amyotrophic Lateral Sclerosis
Transforming Growth Factor beta
Skeletal Muscle
Fibrosis
skeletal muscle
Aldehyde Oxidoreductases
mice
fibrosis
Extracellular Matrix
platelet-derived growth factor
transforming growth factor beta
sclerosis
extracellular matrix
Platelet-Derived Growth Factor alpha Receptor
Muscles
Enzyme Reactivators
Supravalvular Aortic Stenosis
muscles
receptors
cells

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Citar esto

Gonzalez, D., Contreras, O., Rebolledo, D. L., Espinoza, J. P., Van Zundert, B., & Brandan, E. (2017). ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers. PLoS ONE, 12(5), [e0177649]. DOI: 10.1371/journal.pone.0177649

Gonzalez, David; Contreras, Osvaldo; Rebolledo, Daniela L.; Espinoza, Juan Pablo; Van Zundert, Brigitte; Brandan, Enrique / ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers.

En: PLoS ONE, Vol. 12, N.º 5, e0177649, 01.05.2017.

Resultado de la investigación: Contribución a la publicaciónArticle

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Gonzalez, D, Contreras, O, Rebolledo, DL, Espinoza, JP, Van Zundert, B & Brandan, E 2017, 'ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers' PLoS ONE, vol. 12, n.º 5, e0177649. DOI: 10.1371/journal.pone.0177649

ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers. / Gonzalez, David; Contreras, Osvaldo; Rebolledo, Daniela L.; Espinoza, Juan Pablo; Van Zundert, Brigitte; Brandan, Enrique.

En: PLoS ONE, Vol. 12, N.º 5, e0177649, 01.05.2017.

Resultado de la investigación: Contribución a la publicaciónArticle

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Gonzalez D, Contreras O, Rebolledo DL, Espinoza JP, Van Zundert B, Brandan E. ALS skeletal muscle shows enhanced TGF-β signaling, fibrosis and induction of fibro/adipogenic progenitor markers. PLoS ONE. 2017 may 1;12(5). e0177649. Disponible desde, DOI: 10.1371/journal.pone.0177649