An Investigation of Dasatinib and Quercetin as Enhancers of Myofiber Regeneration in DMD

Abstract

Ineffective myofiber repair mechanisms in Duchenne's Muscular Dystrophy (DMD) result in progressive muscle tissue degeneration. DMD aligns with 8 of the 12 hallmarks of aging, with the presence of senescent cells and stem cell exhaustion severely impairing regenerative capacity. As muscle cells are progressively lost and replaced by fat deposits and fibrosis, secondary mechanisms of the disease give rise to phenotypes associated with premature aging that worsen over time. This study aims to improve regenerative capacity in DMD mouse myofibers by administering the senolytics Dasatinib and Quercetin (D+Q). D+Q was administered to mice at 4 weeks of age for a period of 21 weeks through oral gavage. Mice were sacrificed at 25 weeks of age, and the Flexor Digitorum Brevis (FDB) muscle myofibers will be isolated and cultured to observe the satellite cell migration and proliferation patterns for 48 hrs. Cell counts and migration distance calculations were performed at 24 hrs and 48 hrs compared to healthy controls. Fibers were fixed at 48 hrs for immunostaining of satellite cell markers, ATPB, and H2AX. Fibers from D+Q treated mdx mice did not have significant differences in the number of cells that migrated away from the fibers compared to their respective untreated mdx mice. This study is ongoing, and the fibers are being further evaluated for differences in satellite cell content using immunofluorescence markers.