Cardiac progenitors in Duchenne muscular dystrophy show elevated DNA damage and accelerated maturation
| Autoři | |
|---|---|
| Rok publikování | 2026 |
| Druh | Konferenční abstrakty |
| Fakulta / Pracoviště MU | |
| Citace | |
| Přiložené soubory | |
| Popis | Duchenne muscular dystrophy (DMD) is a rare, X-linked neuromuscular disorder caused by dystrophin mutations, which result in progressive skeletal muscle loss followed by cardiomyopathy. Current medical care is palliative; interventions and improved therapies require further research. We previously showed that DMD already affects the pluripotent stem cell (PSC) stage through elevated DNA damage and mutagenesis, at least partially caused by deregulated nitric oxide synthase (NOS) and production of reactive species. Given these results, we questioned how that affects cardiac tissue development. DMD cardiovascular progenitor (CP) population in developing cardiac organoids shows an altered transcriptional program during differentiation. CP markers activate earlier, followed by earlier onset of maturation-related gene expression and ongoing inflammation. DMD CPs present higher levels of DNA damage and lowered proliferation. These early deregulations are followed by impaired cardiac differentiation efficacy with higher rate of cardiomyocyte (CM) death as well as increased and accelerated collagen deposition, thus recapitulating the phenotype of mdx mouse and human DMD hearts. NOS inhibition attenuates DNA damage in CPs, rescues CP proliferation and improves formation of beating organoids; however, it does not prevent CM death or significantly affect transcription of cardiac development-related genes. Thus, with further study, NOS inhibition may complement current medical care. Project was funded by project National Institute for Research of Metabolic and Cardiovascular Diseases (Programme EXCELES, ID Project No. LX22NPO5104) – Funded by the European Union – Next Generation EU. |
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