Cargando…
Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators
BACKGROUND: Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the la...
Autores principales: | , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995146/ https://www.ncbi.nlm.nih.gov/pubmed/32007101 http://dx.doi.org/10.1186/s13395-020-0221-2 |
_version_ | 1783493326900559872 |
---|---|
author | Lindsay, Angus Baumann, Cory W. Rebbeck, Robyn T. Yuen, Samantha L. Southern, William M. Hodges, James S. Cornea, Razvan L. Thomas, David D. Ervasti, James M. Lowe, Dawn A. |
author_facet | Lindsay, Angus Baumann, Cory W. Rebbeck, Robyn T. Yuen, Samantha L. Southern, William M. Hodges, James S. Cornea, Razvan L. Thomas, David D. Ervasti, James M. Lowe, Dawn A. |
author_sort | Lindsay, Angus |
collection | PubMed |
description | BACKGROUND: Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECC-induced strength loss of dystrophin-deficient mouse skeletal muscle (10–95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC. METHODS: We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured sarcolemmal damage after ECC as well as strength loss in the presence of the antioxidant N-acetylcysteine (NAC) and small molecule calcium modulators that increase SERCA activity (DS-11966966 and CDN1163) or lower calcium leak from the ryanodine receptor (Chloroxine and Myricetin). RESULTS: The magnitude of length change, work, and stimulation duration ex vivo and in vivo of an ECC were the most important determinants of strength loss in mdx muscle. Passive lengthening and submaximal stimulations did not induce strength loss. We further showed that sarcolemmal permeability was associated with muscle length change, but it only accounted for a minimal fraction (21%) of the total strength loss (70%). The magnitude of length change also significantly influenced the degree to which NAC and small molecule calcium modulators protected against ECC-induced strength loss. CONCLUSIONS: These results indicate that ECC-induced strength loss of mdx skeletal muscle is dependent on the mechanical properties of the contraction and that mdx muscle is insensitive to ECC at submaximal stimulation frequencies. Rigorous design of ECC protocols is critical for effective use of strength loss as a readout in evaluating potential therapeutics for muscular dystrophy. |
format | Online Article Text |
id | pubmed-6995146 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-69951462020-02-04 Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators Lindsay, Angus Baumann, Cory W. Rebbeck, Robyn T. Yuen, Samantha L. Southern, William M. Hodges, James S. Cornea, Razvan L. Thomas, David D. Ervasti, James M. Lowe, Dawn A. Skelet Muscle Research BACKGROUND: Dystrophin deficiency sensitizes skeletal muscle of mice to eccentric contraction (ECC)-induced strength loss. ECC protocols distinguish dystrophin-deficient from healthy, wild type muscle, and test the efficacy of therapeutics for Duchenne muscular dystrophy (DMD). However, given the large lab-to-lab variability in ECC-induced strength loss of dystrophin-deficient mouse skeletal muscle (10–95%), mechanical factors of the contraction likely impact the degree of loss. Therefore, the purpose of this study was to evaluate the extent to which mechanical variables impact sensitivity of dystrophin-deficient mouse skeletal muscle to ECC. METHODS: We completed ex vivo and in vivo muscle preparations of the dystrophin-deficient mdx mouse and designed ECC protocols within physiological ranges of contractile parameters (length change, velocity, contraction duration, and stimulation frequencies). To determine whether these contractile parameters affected known factors associated with ECC-induced strength loss, we measured sarcolemmal damage after ECC as well as strength loss in the presence of the antioxidant N-acetylcysteine (NAC) and small molecule calcium modulators that increase SERCA activity (DS-11966966 and CDN1163) or lower calcium leak from the ryanodine receptor (Chloroxine and Myricetin). RESULTS: The magnitude of length change, work, and stimulation duration ex vivo and in vivo of an ECC were the most important determinants of strength loss in mdx muscle. Passive lengthening and submaximal stimulations did not induce strength loss. We further showed that sarcolemmal permeability was associated with muscle length change, but it only accounted for a minimal fraction (21%) of the total strength loss (70%). The magnitude of length change also significantly influenced the degree to which NAC and small molecule calcium modulators protected against ECC-induced strength loss. CONCLUSIONS: These results indicate that ECC-induced strength loss of mdx skeletal muscle is dependent on the mechanical properties of the contraction and that mdx muscle is insensitive to ECC at submaximal stimulation frequencies. Rigorous design of ECC protocols is critical for effective use of strength loss as a readout in evaluating potential therapeutics for muscular dystrophy. BioMed Central 2020-02-01 /pmc/articles/PMC6995146/ /pubmed/32007101 http://dx.doi.org/10.1186/s13395-020-0221-2 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Lindsay, Angus Baumann, Cory W. Rebbeck, Robyn T. Yuen, Samantha L. Southern, William M. Hodges, James S. Cornea, Razvan L. Thomas, David D. Ervasti, James M. Lowe, Dawn A. Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title | Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title_full | Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title_fullStr | Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title_full_unstemmed | Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title_short | Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
title_sort | mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995146/ https://www.ncbi.nlm.nih.gov/pubmed/32007101 http://dx.doi.org/10.1186/s13395-020-0221-2 |
work_keys_str_mv | AT lindsayangus mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT baumanncoryw mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT rebbeckrobynt mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT yuensamanthal mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT southernwilliamm mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT hodgesjamess mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT cornearazvanl mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT thomasdavidd mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT ervastijamesm mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators AT lowedawna mechanicalfactorstunethesensitivityofmdxmuscletoeccentricstrengthlossanditsprotectionbyantioxidantandcalciummodulators |