Abstract P2117: TRF2 Rescues Pathogenic Phenotypes In Duchenne Muscular Dystrophy Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart; however, these treatments do not address the root cause of dilated cardiomyopathy: loss of cardiomyocytes. Previously, we showed that longer telomeres are protective against dilated cardiomyopathy. Here we investigated the role of telomeres as a target for therapy in DMD cardiomyocytes using human induced pluripotent stem cells (iPSCs) to model the disease. Compared to healthy controls, DMD cardiomyocytes exhibited reduced telomere lengths, cell size, nuclear size, and sarcomere density. The telomere-binding protein, TRF2, is a core component of the shelterin complex, which protects chromosome ends. TRF2 levels are reduced relative to healthy controls in DMD cardiomyocytes. We hypothesized that decreased TRF2 drives telomere attrition in the progression of dilated cardiomyopathy. Our data show that TRF2 overexpression prevented telomere attrition and also rescued deficits in cell size, nuclear size, sarcomere density, and calcium handling. These data highlight the benefits of TRF2 upregulation as a potential gene therapy to delay the onset of dilated cardiomyopathy.