Social stress is lethal in the mdx model of Duchenne muscular dystrophy

Maria Razzoli, Angus Lindsay, Michelle L. Law, Christopher M. Chamberlain, William M. Southern, Madeleine Berg, John Osborn, William C. Engeland, Joseph M. Metzger, James M. Ervasti, Alessandro Bartolomucci

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Background: Duchenne muscular dystrophy (DMD) is caused by the loss of dystrophin. Severe and ultimately lethal, DMD progresses relatively slowly in that patients become wheelchair bound only around age twelve with a survival expectancy reaching the third decade of life. Methods: The mildly-affected mdx mouse model of DMD, and transgenic DysΔMTB-mdx and Fiona-mdx mice expressing dystrophin or utrophin, respectively, were exposed to either mild (scruffing) or severe (subordination stress) stress paradigms and profiled for their behavioral and physiological responses. A subgroup of mdx mice exposed to subordination stress were pretreated with the beta-blocker metoprolol. Findings: Subordination stress caused lethality in ∼30% of mdx mice within 24 h and ∼70% lethality within 48 h, which was not rescued by metoprolol. Lethality was associated with heart damage, waddling gait and hypo-locomotion, as well as marked up-regulation of the hypothalamus-pituitary-adrenocortical axis. A novel cardiovascular phenotype emerged in mdx mice, in that scruffing caused a transient drop in arterial pressure, while subordination stress caused severe and sustained hypotension with concurrent tachycardia. Transgenic expression of dystrophin or utrophin in skeletal muscle protected mdx mice from scruffing and social stress-induced responses including mortality. Interpretation: We have identified a robust new stress phenotype in the otherwise mildly affected mdx mouse that suggests relatively benign handling may impact the outcome of behavioural experiments, but which should also expedite the knowledge-based therapy development for DMD. Funding: Greg Marzolf Jr. Foundation, Summer's Wish Fund, NIAMS, Muscular Dystrophy Association, University of Minnesota and John and Cheri Gunvalson Trust.

Original languageEnglish (US)
Article number102700
JournalEBioMedicine
Volume55
DOIs
StatePublished - May 2020

Bibliographical note

Publisher Copyright:
© 2020 The Authors

Keywords

  • HPA-axis
  • Hypertension
  • Muscular dystrophy
  • Social stress
  • Utrophin

PubMed: MeSH publication types

  • Journal Article

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