Potential therapeutic target for DMD-associated cardiomyopathy : SHP2
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Duchenne Muscular Dystrophy (DMD) is a severe degenerative muscle disorder caused by deletion, duplication, or point mutation in the gene encoding dystrophin. As advancements in respiratory support have increased DMD patient lifespan, dilated cardiomyopathy has become a concerning source of morbidity and mortality in DMD, underscoring the need for further research in this area. Pilot data from our lab has shown that Src homology region 2 domain-containing phosphatase-2 (SHP2) inhibition may have cardioprotective effects. SHP2 is a protein tyrosine phosphatase that dephosphorylates proteins involved in several cellular processes. We investigated the potential beneficial effects of SHP2 inhibition through analysis of cardiac muscle function and histology in DMD mice. To genetically reduce SHP2 activity, we generated mice that express dominant negative SHP2 (dnSHP2) in cardiac myocytes. For this project, dnSHP2 mice were crossed with Dmdmdx-4Cv (referred to throughout as mdx) mice to determine the extent of the hypothesized protective effects. To quantify fibrosis, hearts from 18+ months old mice were fixed with 4% paraformaldehyde in cardioplegic buffer and sections stained with Gomori trichrome. To compare ejection fraction, fractional shortening, and chamber dimensions between control (wildtype with/without dnSHP2) and experimental groups (mdx with/without dnSHP2), anesthetized 4--7-month-old mice underwent high-resolution echocardiography. After acclimatization, conscious echocardiography was performed on mice aged 22-24 months. Data collected show a significant reduction in left ventricular fibrosis in dnSHP2; mdx/y mice. Additionally, dnSHP2; mdx/y mice exhibit marked improvements in ejection fraction and fractional shortening compared to non-transgenic (NTG) mdx/y mice. These improvements were particularly pronounced in the aged cohort. The cardioprotective effects observed support additional investigation into SHP2 as a possible therapeutic target.
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M.S.