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

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A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats (1).pdf (1.35 MB)
Date
2021-09-01
Authors
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0000-0002-9643-1037
 https://orcid.org/0000-0003-1838-4279
 https://orcid.org/0000-0002-7610-4231
 https://doi.org/10.1096/fj.202100711RR
Journal Title
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Volume Title
Publisher
Wiley Open Access
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35
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URI
http://hdl.handle.net/20.500.12254/2234
Abstract
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.
Description
The current study was funded by a generous gift from the BertinBarbe Family to HZF, and KB. The work was further supported by the National Institute of Aging through project grants (R01AG056999 and R01AG45375). AAM was supported by a postdoctoral fellowship from Deutsche Forschungsgemeinschaft
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Citation
Langer HT, Mossakowski AA, Avey AM, et al. A mutation in desmin makes skeletal muscle less vulnerable to acute muscle damage after eccentric loading in rats. FASEB J. 2021;35:e21860. https://doi.org/10.1096/fj.20210 0711RR
Keywords
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Atribución-NoComercial-SinDerivadas 4.0 Internacional (CC BY-NC-ND 4.0)
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https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
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