DMD – ANIMAL MODELS: EP.85 Oestrogen and HPA/renin-angiotensin-aldosterone pathways are associated with the behavioural sensitivity to stress in dystrophin-deficient mice

Abstract

Mutation to the dystrophin gene can increase the sensitivity to behavioural stress in vertebrates, including the mdx mouse model of Duchenne muscular dystrophy. Hyper-sensitivity to behavioural stress in mdx mice can exacerbate some dystrophinopathy phenotypes and cause hypotension-induced death. However, using a large-scale screen of male and female mdx mice, we have discovered a sub-population that show wildtype-like responses to mild (forced downhill treadmill exercise) and moderate (scruff-restraint) behavioural stress. These “stress resistant” mdx mice are more physically active, capable of super-activating the hypothalamic-pituitary-adrenal (HPA) and renin-angiotensin-aldosterone (RAAS) pathways following behavioural stress and they express greater levels of mineralocorticoid and glucocorticoid receptors in striated muscle relative to “stress-sensitive” mdx mice. At rest, “stress-resistant” mdx mice had a less severe striated muscle histopathology, including fewer central nucleated fibres, less fibrosis, greater vascular density, elevated expression levels of utrophin and greater exercise and skeletal muscle oxidative capacity. Most interestingly, female mdx mice were more “stress resistant”, as indicated by a greater level of physically activity following forced downhill treadmill exercise and scruff-restraint, relative to male mdx mice. Stress-resistance was completely abolished after ovariectomy. Replacement of oestradiol in ovariectomized female mdx mice completely rescued their “stress resistance”, again indicated by a greater physical activity response following forced downhill treadmill exercise, but not to scruff-restraint. Our data demonstrate that the differential sensitivity to behavioural stress in mdx mice is linked to oestrogen, activation of the HPA axis and the RAAS pathway and associated with striated muscle pathophysiology.