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Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor

In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture dur...

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Autores principales: Brashear, Sarah E., Wohlgemuth, Ross P., Hu, Lin-Ya, Jbeily, Elias H., Christiansen, Blaine A., Smith, Lucas R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612445/
https://www.ncbi.nlm.nih.gov/pubmed/36302059
http://dx.doi.org/10.1371/journal.pone.0271776
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author Brashear, Sarah E.
Wohlgemuth, Ross P.
Hu, Lin-Ya
Jbeily, Elias H.
Christiansen, Blaine A.
Smith, Lucas R.
author_facet Brashear, Sarah E.
Wohlgemuth, Ross P.
Hu, Lin-Ya
Jbeily, Elias H.
Christiansen, Blaine A.
Smith, Lucas R.
author_sort Brashear, Sarah E.
collection PubMed
description In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture during fibrosis that relate more closely to functional muscle stiffness. One of these architectural changes in dystrophic muscle is collagen cross-linking, which has been shown to increase the passive muscle stiffness in models of fibrosis including the mdx mouse, a model of DMD. We tested whether the intraperitoneal injections of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking enzyme lysyl oxidase, would reduce collagen cross-linking and passive stiffness in young and adult mdx mice compared to saline-injected controls. We found no significant differences between BAPN treated and saline treated mice in collagen cross-linking and stiffness parameters. However, we observed that while collagen cross-linking and passive stiffness scaled positively in dystrophic muscles, collagen fiber alignment scaled with passive stiffness distinctly between muscles. We also observed that the dystrophic diaphragm showed the most dramatic fibrosis in terms of collagen content, cross-linking, and stiffness. Overall, we show that while BAPN was not effective at reducing collagen cross-linking, the positive association between collagen cross-linking and stiffness in dystrophic muscles still show cross-linking as a viable target for reducing passive muscle stiffness in DMD or other fibrotic muscle conditions.
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spelling pubmed-96124452022-10-28 Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor Brashear, Sarah E. Wohlgemuth, Ross P. Hu, Lin-Ya Jbeily, Elias H. Christiansen, Blaine A. Smith, Lucas R. PLoS One Research Article In Duchenne muscular dystrophy (DMD), a lack of functional dystrophin leads to myofiber instability and progressive muscle damage that results in fibrosis. While fibrosis is primarily characterized by an accumulation of extracellular matrix (ECM) components, there are changes in ECM architecture during fibrosis that relate more closely to functional muscle stiffness. One of these architectural changes in dystrophic muscle is collagen cross-linking, which has been shown to increase the passive muscle stiffness in models of fibrosis including the mdx mouse, a model of DMD. We tested whether the intraperitoneal injections of beta-aminopropionitrile (BAPN), an inhibitor of the cross-linking enzyme lysyl oxidase, would reduce collagen cross-linking and passive stiffness in young and adult mdx mice compared to saline-injected controls. We found no significant differences between BAPN treated and saline treated mice in collagen cross-linking and stiffness parameters. However, we observed that while collagen cross-linking and passive stiffness scaled positively in dystrophic muscles, collagen fiber alignment scaled with passive stiffness distinctly between muscles. We also observed that the dystrophic diaphragm showed the most dramatic fibrosis in terms of collagen content, cross-linking, and stiffness. Overall, we show that while BAPN was not effective at reducing collagen cross-linking, the positive association between collagen cross-linking and stiffness in dystrophic muscles still show cross-linking as a viable target for reducing passive muscle stiffness in DMD or other fibrotic muscle conditions. Public Library of Science 2022-10-27 /pmc/articles/PMC9612445/ /pubmed/36302059 http://dx.doi.org/10.1371/journal.pone.0271776 Text en © 2022 Brashear et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Brashear, Sarah E.
Wohlgemuth, Ross P.
Hu, Lin-Ya
Jbeily, Elias H.
Christiansen, Blaine A.
Smith, Lucas R.
Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title_full Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title_fullStr Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title_full_unstemmed Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title_short Collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
title_sort collagen cross-links scale with passive stiffness in dystrophic mouse muscles, but are not altered with administration of a lysyl oxidase inhibitor
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9612445/
https://www.ncbi.nlm.nih.gov/pubmed/36302059
http://dx.doi.org/10.1371/journal.pone.0271776
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