DUCHENNE MUSCULAR DYSTROPHY: CARDIAC PHENOTYPE AS A RESULT OF DNA DAMAGE-INDUCED CHANGE OF STEM CELL FATE.

Duchenne muscular dystrophy (DMD) is caused by impaired dystrophin. Majority of the DMD patients suffer from cardiomyopathy, arrhythmias, and heart failure is the predominant cause of death. However, many works showed the molecular mechanisms leading to the DMD cardiomyocyte death during recent decades, and the delayed onset of progressive cardiomyopathy is still unclear. Recently was implicated the involvement of progenitor population failure destabilizing muscle homeostasis and inducing progressive muscle wasting. DMD patient-specific induced pluripotent stem cell model and human embryonic stem cells with dystrophin mutation introduced by CRISPR/Cas technology (DMD hPSC for both models) were used to uncover the involvement of cardiac progenitor cells (CPCs) depletion and its mechanism in humans to cardiac failure. The absence of dystrophin in DMD hPSC resulted in dysregulation of nitric oxide synthase (NOS), which in turn spiked the excessive release of reactive oxygen species (ROS). We show that ROS are associated with increased DNA damage and elevated mutant frequency in DMD hPSCs. Scavenging the ROS and/or inhibition of NOS resulted in DNA damage reduction. Contrary to WT mouse hearts was observed a dramatic increase in CPCs population in young adult (2-3 months) MDX mice hearts is followed by a steep decrease in mature animals. CPCs depletion in MDX animal hearts is associated with elevated nuclear DNA damage.

The elevated proliferation of CPCs together with NOS induced-ROS mediated-genomic instability leads to CPCs depletion, and subsequently to limited ability to maintain homeostasis of the heart muscle.

The work was supported by the Eu Regional Development Fund-Project ENOCH CZ.02.1.01/0.0/0.0/16_019/0000868; by National Institute for Research of Metabolic and Cardiovascular Diseases EXCELES, ID LX22NPO5104 funded by "Next Generation EU".