In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Social stress is lethal in the mdx model of Duchenne muscular dystrophy.
Today’s pick is a paper from 2020 by Razzoli et al in EBioMedicine to which I was alerted by co-author James Ervasti when I virtually visited his group last week. It is about stress induced lethality in mdx mice. Doi 10.1016/j.ebiom.2020.102700
As I have mentioned before, Duchenne is not only a disease of skeletal muscle but also of the heart and the brain. Duchenne patients suffer from chronic cardiomyopathy but can also have acute heart problems. The mdx mouse model is milder – for muscle and heart pathology.
However, it has been shown that mdx mice show a severe fear/hypoactivity response to mild stress (e.g. handling or mild exercise protocols). Here authors investigated what happens after mdx mice are subjected to very severe stress: interaction with very dominant aggressive mice.
Authors first show that after normal handling corticosterone levels in urine are higher in mdx mice than wild type. Then mice are placed (under supervision) in a cage with very aggressive CD1 males for 10 minutes and then put in behind a divider (can see/hear/smell CD1 mouse).
This induces tachycardia (increased heart rate) in both mdx and wild type mice and increased corticosterone production (sign of stress). For mdx mice it took a lot longer for the corticosterone levels to normalize after 1 time exposure to the CD1 mouse (no divider set up)
When mice were exposed to longer term stress, 72% of mdx mice died <48 hours, & 30% <24 hours. Cardiac pathology was observed (fibrosis & immune cell infiltration), but this can have been present before stressor. Increased cardiac troponin levels suggest also acute heart damage.
Authors pretreated mdx and wild type mice with metoprolol (a beta blocker) for 1 week, but this had no effect on lethality in the mdx mice. This suggests the death is not caused by aberrant adrenergic regulation.
Authors studied mean arterial pressure and heart rate. In wild type mice and mdx mice they observed after the stressor that heart rate went up. However, in mdx mice this was accompanied by hypotension which eventually resulted in slower heart rate and death.
Authors then studied response to severe stress in mice with dystrophin expressed only in skeletal muscle or utrophin overexpressed in skeletal muscle. These mice had normal behavior after stress and lethality was partially rescued.
Authors discuss that it seems several mechanisms contribute to the lethality, i.e. heart pathology, acute heart damage and increased stress. However, they do not know exactly what caused the death of the mice.
It is very interesting that restoring dystrophin or overexpressing utrophin only in the skeletal muscle can partially counteract these effects that seem to affect heart and brain. These results are important to take into account for our BIND project experiments.
Very interesting paper and I am happy Jim Ervasti alerted me to it. Also like the use of relevant controls and the fact that authors are transparent about limitations of the study.
Pictures by Annemieke, used with permission.