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Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model
Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500669/ https://www.ncbi.nlm.nih.gov/pubmed/36142754 http://dx.doi.org/10.3390/ijms231810841 |
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author | Ritter, Paul Nübler, Stefanie Buttgereit, Andreas Smith, Lucas R. Mühlberg, Alexander Bauer, Julian Michael, Mena Kreiß, Lucas Haug, Michael Barton, Elisabeth Friedrich, Oliver |
author_facet | Ritter, Paul Nübler, Stefanie Buttgereit, Andreas Smith, Lucas R. Mühlberg, Alexander Bauer, Julian Michael, Mena Kreiß, Lucas Haug, Michael Barton, Elisabeth Friedrich, Oliver |
author_sort | Ritter, Paul |
collection | PubMed |
description | Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from extensor digitorum longus (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in mdx Cmah [Formula: see text] diaphragm was similar to wt mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in mdx Cmah [Formula: see text] diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in mdx Cmah [Formula: see text] single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the mdx Cmah [Formula: see text] genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background. |
format | Online Article Text |
id | pubmed-9500669 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95006692022-09-24 Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model Ritter, Paul Nübler, Stefanie Buttgereit, Andreas Smith, Lucas R. Mühlberg, Alexander Bauer, Julian Michael, Mena Kreiß, Lucas Haug, Michael Barton, Elisabeth Friedrich, Oliver Int J Mol Sci Article Duchenne muscular dystrophy (DMD) is a degenerative genetic myopathy characterized by complete absence of dystrophin. Although the mdx mouse lacks dystrophin, its phenotype is milder compared to DMD patients. The incorporation of a null mutation in the Cmah gene led to a more DMD-like phenotype (i.e., more fibrosis). Although fibrosis is thought to be the major determinant of ‘structural weakness’, intracellular remodeling of myofibrillar geometry was shown to be a major cellular determinant thereof. To dissect the respective contribution to muscle weakness, we assessed biomechanics and extra- and intracellular architecture of whole muscle and single fibers from extensor digitorum longus (EDL) and diaphragm. Despite increased collagen contents in both muscles, passive stiffness in mdx Cmah [Formula: see text] diaphragm was similar to wt mice (EDL muscles were twice as stiff). Isometric twitch and tetanic stresses were 50% reduced in mdx Cmah [Formula: see text] diaphragm (15% in EDL). Myofibrillar architecture was severely compromised in mdx Cmah [Formula: see text] single fibers of both muscle types, but more pronounced in diaphragm. Our results show that the mdx Cmah [Formula: see text] genotype reproduces DMD-like fibrosis but is not associated with changes in passive visco-elastic muscle stiffness. Furthermore, detriments in active isometric force are compatible with the pronounced myofibrillar disarray of the dystrophic background. MDPI 2022-09-16 /pmc/articles/PMC9500669/ /pubmed/36142754 http://dx.doi.org/10.3390/ijms231810841 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ritter, Paul Nübler, Stefanie Buttgereit, Andreas Smith, Lucas R. Mühlberg, Alexander Bauer, Julian Michael, Mena Kreiß, Lucas Haug, Michael Barton, Elisabeth Friedrich, Oliver Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title_full | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title_fullStr | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title_full_unstemmed | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title_short | Myofibrillar Lattice Remodeling Is a Structural Cytoskeletal Predictor of Diaphragm Muscle Weakness in a Fibrotic mdx (mdx Cmah(−/−)) Model |
title_sort | myofibrillar lattice remodeling is a structural cytoskeletal predictor of diaphragm muscle weakness in a fibrotic mdx (mdx cmah(−/−)) model |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9500669/ https://www.ncbi.nlm.nih.gov/pubmed/36142754 http://dx.doi.org/10.3390/ijms231810841 |
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