Effects of mutant SHP2 expression on heart function in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy that is caused by a mutation in the dystrophin gene which is located on the X chromosome. DMD affect 1 in 3,600 males at birth. Due to recent advancements in treatment of the skeletal muscle disease, patients with DMD have lengthened lifespans, allowing them to live into their forties. Consequently, the prevalence of heart disease has risen in DMD patients. Dilated cardiomyopathy typically develops during adolescence and progresses to heart failure. SH2 domain-containing tyrosine phosphatase 2 (SHP2) plays a regulatory role in several cell signaling events. Work from our lab has discovered that a loss-offunction mutation in SHP2 improves heart function after transverse aortic banding. I hypothesized that expression of a loss-of-function mutant SHP2 will improve heart function in DMD mice. To test this hypothesis, DMD mice (mdx4CV) were crossed with mutant SHP2 (Q510E-SHP2) mice, and we analyzed the compound offspring, NTG:x/y, NTG:mdx/y, SHP2:x/y and SHP2:mdx/y. Echocardiography and histology were used to determine the effects of mutant SHP2 on contractile performance and cardiac fibrosis. We found that 4-month-old DMD hearts with the SHP2 mutation have similar diastolic and systolic function compared to DMD hearts without the SHP2 mutation. However, there was a trend towards improved diastolic function in SHP2: mdx/y that did not reach statistical significance. At 18-months of age, DMD hearts with the SHP2 mutation did not show significant improvement of fibrosis. However, a small trend towards decreased fibrosis was noted due to mutant SHP2. Based on these data, further studies are needed to conclusively state that mutant SHP2 rescues heart functions in DMD hearts.

Name thesis:degree_name

M.S.

Level thesis:degree_level

Masters

Discipline thesis:degree_discipline

Medical Pharmacology and Physiology (MU)

Grantor dc:publisher

University of Missouri--Columbia

Year dc:date.issued

2022

Author dc:creator

• Chatman, Erick

Advisor dc:contributor.advisor

• Krenz, Maike

Language dc:language.iso

eng, English

DOI

https://doi.org/10.32469/10355/94113

OAI identifier oai:identifier

oai:mospace.umsystem.edu:10355/94113