Mechanical factors tune the sensitivity of mdx muscle to eccentric strength loss and its protection by antioxidant and calcium modulators

Angus Lindsay, Cory W. Baumann, Robyn T. Rebbeck, Samantha L. Yuen, William M. Southern, James S. Hodges, Razvan L. Cornea, David D. Thomas, James M. Ervasti, Dawn A. Lowe

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Article number3
JournalSkeletal muscle
Volume10
Issue number1
DOIs
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
This work was supported by the National Institutes of Health grants to J.M.E. (R01 AR042423 and R01 AR049899), D.D.T. (R37 AG26160), and R.L.C (R01 HL138539 and R01 HL092097) and the American Heart Association grant to R.T.R. (16POST31010019). C.W.B. and W.M.S. were supported by the NIH Training Program in Muscle Research (T32AR007612).

Keywords

  • Dystrophin
  • Eccentric contraction
  • Force drop
  • Muscle damage
  • Oxidative stress
  • Ryanodine receptor
  • SERCA
  • Skeletal muscle

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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