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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 and Lowe, Dawn A 2020, Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators, Skeletal muscle, vol. 10, no. 1, pp. 1-14, doi: 10.1186/s13395-020-0221-2.

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Title Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators
Author(s) Lindsay, AngusORCID iD for Lindsay, Angus orcid.org/0000-0002-5195-1901
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
Journal name Skeletal muscle
Volume number 10
Issue number 1
Article ID 3
Start page 1
End page 14
Total pages 14
Publisher BioMed Central
Place of publication London, Eng.
Publication date 2020-02-01
ISSN 2044-5040
2044-5040
Keyword(s) Science & Technology
Life Sciences & Biomedicine
Cell Biology
Dystrophin
Eccentric contraction
Force drop
Muscle damage
Oxidative stress
Ryanodine receptor
SERCA
Skeletal muscle
Summary Abstract 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.
Language eng
DOI 10.1186/s13395-020-0221-2
Indigenous content off
HERDC Research category C1 Refereed article in a scholarly journal
Free to Read? Yes
Persistent URL http://hdl.handle.net/10536/DRO/DU:30134734

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.