University of Minnesota Medical School Researchers Find Social Stress is Lethal in a Mouse Model of Duchenne Muscular Dystrophy

MINNEAPOLIS, MN- March 16, 2020 – Duchenne Muscular Dystrophy (DMD) is a rare disease that causes progressive weakness and loss of skeletal and heart muscles. This monogenic disorder is caused by a deficiency in the protein dystrophin.

A team of researchers at the University of Minnesota Medical School led by Alessandro Bartolomucci, PhD, associate professor in the Department of Integrative Biology and Physiology, and James Ervasti, PhD, professor in the Department of Biochemistry, Molecular Biology and Biophysics, recently published a study in EBioMedicine that identifies a novel stress phenotype that is lethal in a mouse model of DMD. The study also includes the teams of Joseph Metzger, PhD, John Osborn, PhD, and William Engeland, PhD.

The study uses the “mdx” mouse model of DMD and a chronic social stress model previously developed by the Bartolomucci lab, which increases the animal’s heart rate and blood pressure among other physiological responses. The study was designed to test the vulnerability of the “mdx” mouse model when under chronic social stress.

“We found that the ‘mdx’ mouse was very vulnerable to stress. About 70% of the population studied died in less than 48 hours with widespread damage to the heart and skeletal muscles,” Bartolomucci said. “But, the most striking defect associated with the lethality was very unexpected and consisted of an increase in heart rate but a significant drop in blood pressure.”

The adaptive response to stress includes a concurrent increase in heart rate and in blood pressure to cope with the challenge, as part of the classic fight-or-flight response. However, the “mdx” mouse fails this adaptive response because heart rate goes up, but blood pressure goes down. The lethality is likely due to the animal not being able to recover from the mismatch between the demand and the supply of blood to the organs. Importantly, while the research did not study patients affected by DMD, recent clinical reports have noted that patients affected by DMD can manifest low blood pressure, thus raising the possibility that the new phenotype observed in the “mdx” model may be translationally relevant.

“The study indicates that stress can be detrimental, not only when there is an exaggerated response but also when there is a failure of an adaptive response,” Bartolomucci said.

The team also demonstrated that re-expression of dystrophin protected “mdx” mice from death and prevented the hypotension caused by stress.

“This study helps illustrate the complexities of dystrophic skeletal and cardiac muscle effects on the cardiovascular system. The findings in this report will be important to address in order to advance effective muscular dystrophy therapies from the lab to the patient,” Metzger said.

“Identifying such rapid onset phenotypes in the ‘mdx’ mouse model can also speed up the process of testing new treatments for DMD,” Ervasti said.

The team hopes it will accelerate biomedical research and offer a new protocol for studying the vulnerability of this mouse model and a new cardiovascular phenotype. Next steps include further research to explore the translation of this phenotype to humans and the identification of the molecular mechanisms linking the stress response to hypotension.

The study was a collaboration within the University of Minnesota Medical School and the Paul and Sheila Wellstone Muscular Dystrophy Center. The study was supported by the Greg Marzolf Jr. Foundation, Summer’s Wish Fund, the Muscular Dystrophy Association and the National Institutes of Health.

Razzoli M, Lindsay A, Law ML, Chamberlain CM, Chamberlain JS, Engeland WC, Metzger JM, Ervasti JM, Bartolomucci A. Social stress is lethal in the mdx model of Duchenne Muscular Dystrophy. EBioMedicine, 2020.

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