ABSTRACT
A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.
Subject(s)
Circulating MicroRNA , MicroRNAs , Radiation Injuries , Humans , Animals , Mice , MicroRNAs/genetics , Mice, Inbred C57BL , Biomarkers , Circulating MicroRNA/genetics , Radiation Injuries/diagnosis , Radiation Injuries/genetics , Gene Expression ProfilingABSTRACT
DNA integrity is incessantly confronted to agents inducing DNA lesions. All organisms are equipped with a network of DNA damage response mechanisms that will repair DNA lesions and restore proper cellular activities. Despite DNA repair mechanisms have been revealed in replicating cells, still little is known about how DNA lesions are repaired in postmitotic cells. Muscle fibers are highly specialized postmitotic cells organized in syncytia and they are vulnerable to age-related degeneration and atrophy after radiotherapy treatment. We have studied the DNA repair capacity of muscle fiber nuclei and compared it with the one measured in proliferative myoblasts here. We focused on the DNA repair mechanisms that correct ionizing radiation (IR)-induced lesions, namely the base excision repair, the nonhomologous end joining, and the homologous recombination (HR). We found that in the most differentiated myogenic cells, myotubes, these DNA repair mechanisms present weakened kinetics of recruitment of DNA repair proteins to IR-damaged DNA. For base excision repair and HR, this decline can be linked to reduced steady-state levels of key proteins involved in these processes.
