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

EBioMedicine. 2020 May;55:102700. doi: 10.1016/j.ebiom.2020.102700. Epub 2020 Mar 16.

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.

Keywords: HPA-axis; Hypertension; Muscular dystrophy; Social stress; Utrophin.

MeSH terms

  • Adrenergic beta-Antagonists / pharmacology
  • Animals
  • Arterial Pressure / drug effects
  • Disease Models, Animal
  • Dystrophin / genetics*
  • Dystrophin / metabolism
  • Gait Disorders, Neurologic / complications
  • Gait Disorders, Neurologic / genetics
  • Gait Disorders, Neurologic / mortality*
  • Gait Disorders, Neurologic / physiopathology
  • Gene Expression
  • Heart Failure / complications
  • Heart Failure / genetics
  • Heart Failure / mortality*
  • Heart Failure / physiopathology
  • Humans
  • Hypotension / complications
  • Hypotension / genetics
  • Hypotension / mortality
  • Hypotension / physiopathology
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypothalamo-Hypophyseal System / physiopathology
  • Male
  • Metoprolol / pharmacology
  • Mice
  • Mice, Inbred mdx
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiopathology
  • Muscular Dystrophy, Duchenne / complications
  • Muscular Dystrophy, Duchenne / genetics
  • Muscular Dystrophy, Duchenne / mortality*
  • Muscular Dystrophy, Duchenne / physiopathology
  • Stress, Psychological / complications
  • Stress, Psychological / genetics
  • Stress, Psychological / mortality*
  • Stress, Psychological / physiopathology
  • Survival Analysis
  • Tachycardia / complications
  • Tachycardia / genetics
  • Tachycardia / mortality
  • Tachycardia / physiopathology
  • Transgenes
  • Utrophin / genetics*
  • Utrophin / metabolism

Substances

  • Adrenergic beta-Antagonists
  • Dystrophin
  • Utrophin
  • Metoprolol