Some dystrophy phenotypes of dystrophin-deficient mdx mice are exacerbated by mild, repetitive daily stress

Research output: Contribution to journalArticlepeer-review

Abstract

Psychosocial stressors can cause physical inactivity, cardiac damage, and hypotension-induced death in the mdx mouse model of Duchenne muscular dystrophy (DMD). Because repeated exposure to mild stress can lead to habituation in wild-type mice, we investigated the response of mdx mice to a mild, daily stress to determine whether habituation occurred. Male mdx mice were exposed to a 30-sec scruff restraint daily for 12 weeks. Scruff restraint induced immediate physical inactivity that persisted for at least 60 minutes, and this inactivity response was just as robust after 12 weeks as it was after one day. Physical inactivity in the mdx mice was not associated with acute skeletal muscle contractile dysfunction. However, skeletal muscle of mdx mice that were repeatedly stressed had slow-twitch and tetanic relaxation times and trended toward high passive stiffness, possibly due to a small but significant increase in muscle fibrosis. Elevated urinary corticosterone secretion, adrenal hypertrophy, and a larger adrenal cortex indicating chronic activation of the hypothalamic-pituitary-adrenal (HPA) axis were measured in 12-week stressed mdx mice relative to those unstressed. However, pharmacological inhibition of the HPA axis did not affect scruff-induced physical inactivity and acute corticosterone injection did not recapitulate the scruff-induced phenotype, suggesting the HPA axis is not the driver of physical inactivity. Our results indicate that the response of mdx mice to an acute mild stress is non-habituating and that when that stressor is repeated daily for weeks, it is sufficient to exacerbate some phenotypes associated with dystrophinopathy in mdx mice.

Original languageEnglish (US)
Article numbere21489
JournalFASEB Journal
Volume35
Issue number4
DOIs
StatePublished - Apr 2021

Bibliographical note

Funding Information:
This work was supported by the University of Minnesota Lillehei Heart Institute, National Institutes of Health R01 AR042423 and R01 AR049899, the Muscular Dystrophy Association (349549), Summer's Wish Foundation, and Greg Marzolf Jr Foundation Research Grant. The authors would like to thank William Engeland for his expert guidance on the study design, Gengyun Le for her help during the scruff restraint experiment and Brittany Collins, and Tara Mader for their help in tissue collection. They also thank the following University of Minnesota Doctorate of Physical Therapy students for their contributions: Jessica Timmons, Nolan Weber, Nou Vang, Beth Wittry, Maria Houle, Hannah Taylor, Anika Theisen and Samanthan Sobolewski.

Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology

Keywords

  • Duchenne muscular dystrophy
  • Dystrophin
  • fibrosis
  • hypothalamic-pituitary-adrenal axis
  • skeletal muscle

PubMed: MeSH publication types

  • Journal Article

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