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A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats

Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we...

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Autores principales: Langer, Henning T., Mossakowski, Agata A., Avey, Alec M., Wohlgemuth, Ross P., Smith, Lucas R., Zbinden‐Foncea, Herman, Baar, Keith
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292853/
https://www.ncbi.nlm.nih.gov/pubmed/34411340
http://dx.doi.org/10.1096/fj.202100711RR
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author Langer, Henning T.
Mossakowski, Agata A.
Avey, Alec M.
Wohlgemuth, Ross P.
Smith, Lucas R.
Zbinden‐Foncea, Herman
Baar, Keith
author_facet Langer, Henning T.
Mossakowski, Agata A.
Avey, Alec M.
Wohlgemuth, Ross P.
Smith, Lucas R.
Zbinden‐Foncea, Herman
Baar, Keith
author_sort Langer, Henning T.
collection PubMed
description Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we stimulated the sciatic nerve of wild‐type littermates (WT) (n = 6) and animals carrying the mutation (MUT) (n = 6) causing a lengthening contraction of the dorsi flexor muscles. MUT animals showed signs of ongoing regeneration at baseline as indicated by a higher number of central nuclei (genotype: P < .0001). While stimulation did not impact central nuclei, we found an increased number of IgG positive fibers (membrane damage indicator) after eccentric contractions with both genotypes (stimulation: P < .01). Interestingly, WT animals displayed a more pronounced increase in IgG positive fibers with stimulation compared to MUT (interaction: P < .05). In addition to altered histology, molecular signaling on the protein level differed between WT and MUT. The membrane repair protein dysferlin decreased with eccentric loading in WT but increased in MUT (interaction: P < .05). The autophagic substrate p62 was increased in both genotypes with loading (stimulation: P < .05) but tended to be more elevated in WT (interaction: P = .05). Caspase 3 levels, a central regulator of apoptotic cell death, was increased with stimulation in both genotypes (stimulation: P < .01) but more so in WT animals (interaction: P < .0001). Overall, our data indicate that R349P Des rats have a lower susceptibility to structural muscle damage of the cytoskeleton and sarcolemma with acute eccentric loading.
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spelling pubmed-92928532022-07-20 A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats Langer, Henning T. Mossakowski, Agata A. Avey, Alec M. Wohlgemuth, Ross P. Smith, Lucas R. Zbinden‐Foncea, Herman Baar, Keith FASEB J Research Articles Desminopathy is the most common intermediate filament disease in humans. The most frequent mutation causing desminopathy in patients is a R350P DES missense mutation. We have developed a rat model with an analogous mutation in R349P Des. To investigate the role of R349P Des in mechanical loading, we stimulated the sciatic nerve of wild‐type littermates (WT) (n = 6) and animals carrying the mutation (MUT) (n = 6) causing a lengthening contraction of the dorsi flexor muscles. MUT animals showed signs of ongoing regeneration at baseline as indicated by a higher number of central nuclei (genotype: P < .0001). While stimulation did not impact central nuclei, we found an increased number of IgG positive fibers (membrane damage indicator) after eccentric contractions with both genotypes (stimulation: P < .01). Interestingly, WT animals displayed a more pronounced increase in IgG positive fibers with stimulation compared to MUT (interaction: P < .05). In addition to altered histology, molecular signaling on the protein level differed between WT and MUT. The membrane repair protein dysferlin decreased with eccentric loading in WT but increased in MUT (interaction: P < .05). The autophagic substrate p62 was increased in both genotypes with loading (stimulation: P < .05) but tended to be more elevated in WT (interaction: P = .05). Caspase 3 levels, a central regulator of apoptotic cell death, was increased with stimulation in both genotypes (stimulation: P < .01) but more so in WT animals (interaction: P < .0001). Overall, our data indicate that R349P Des rats have a lower susceptibility to structural muscle damage of the cytoskeleton and sarcolemma with acute eccentric loading. John Wiley and Sons Inc. 2021-08-19 2021-09 /pmc/articles/PMC9292853/ /pubmed/34411340 http://dx.doi.org/10.1096/fj.202100711RR Text en © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Langer, Henning T.
Mossakowski, Agata A.
Avey, Alec M.
Wohlgemuth, Ross P.
Smith, Lucas R.
Zbinden‐Foncea, Herman
Baar, Keith
A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title_full A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title_fullStr A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title_full_unstemmed A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title_short A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
title_sort mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9292853/
https://www.ncbi.nlm.nih.gov/pubmed/34411340
http://dx.doi.org/10.1096/fj.202100711RR
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