Radiosensitivity and delayed radiation-induced nucleo-shuttling of the ATM protein in fibroblasts from Duchenne muscular dystrophy expressing residual dystrophin

Duchenne muscular dystrophy (DMD) is the most common and severe muscle disorder in children, primarily affecting boys, with an incidence of 1 among 5000. This X-linked recessive disease is marked by progressive muscle wasting, leading to loss of ambulation, respiratory impairment, and cardiomyopathy, with symptoms appearing between ages 2 and 5. While advances in care have extended the life expectancy of DMD patients to 30-40 years, cardiac and respiratory failure often leads to mortality by age 40. DMD is caused by mutations in the DMD gene, encoding the dystrophin protein, essential for muscle fiber integrity. Some studies performed between the 1980s and 1990s reported significant cellular radiosensitivity in DMD cells, though the mechanisms remained unclear. As a first approach, we investigated whether our Radiation-Induced ATM Nucleo-Shuttling (RIANS) model that describes individual molecular and cellular responses to radiation in fibroblasts of different origins may be also relevant for DMD fibroblasts. We observed moderate but significant cellular radiosensitivity, a high yield of micronuclei, and delayed ATM nucleo-shuttling, indicating impaired DNA double-strand breaks recognition. This delay may be consistent with the sequestration of ATM around the nucleus by mutated dystrophin, forming pATM perinuclear crowns, an accelerated aging biomarker. Such data provide a unified molecular and cellular characterization of radiation response in DMD fibroblasts that should be investigated further.