Total-Body Irradiation and Muscular Damage: A New Model of Radiation Combined Injury in Rats

The potential use of tactical nuclear weapons or improvised nuclear devices in conflict scenarios could cause mass casualties, exposing victims to both physical trauma and ionizing radiation, resulting in complex injuries related to irradiation. Due to the synergistic and deleterious effects of radiation combined injuries, including higher mortality and impaired tissue repair, these injuries must be considered in victim management and triage strategies. While muscle injuries are often reported in conflict zones, their interaction with total-body irradiation (TBI) remains poorly understood. In this study, we developed a new in vivo rat model combining total-body irradiation with localized muscle injury. Animals were exposed to 8 Gy of gamma radiation from a cobalt-60 source, causing hematopoietic acute radiation syndrome (H-ARS). Muscle injury was induced by intramuscular injection of notexin into the left soleus muscle. Clinical assessments were performed at multiple time points over 63 days after irradiation and/or muscle injury, with blood, bone marrow, and muscle samples harvested. Total-body irradiation alone caused about 15% lethality, significant weight loss, and temporary bone marrow aplasia, consistent with H-ARS. Notexin-induced muscle injury caused acute muscle necrosis followed by complete regeneration, as shown by the restoration of muscle mass and normal tissue structure. However, under the combined radiation and injury condition, muscle regeneration was markedly impaired. By day 63, the animals had lost about 20% of muscle mass, with ongoing necrotic fibers, chronic inflammation, thickening of the extracellular matrix in the perimysium, and smaller myofibers, indicating long-term functional impairment. This preclinical model captures radiation combined with muscle injury in the context of H-ARS and shows a lasting impairment of muscle regeneration after irradiation. It offers a useful tool to explore underlying mechanisms and improve medical support during future radiological or nuclear mass casualty events.