Radiation induces long‐term muscle fibrosis and promotes a fibrotic phenotype in fibro‐adipogenic progenitors

Abstract

BackgroundRadiation‐induced muscle pathology, characterized by muscle atrophy and fibrotic tissue accumulation, is the most common debilitating late effect of therapeutic radiation exposure particularly in juvenile cancer survivors. In healthy muscle, fibro/adipogenic progenitors (FAPs) are required for muscle maintenance and regeneration, while in muscle pathology FAPs are precursors for exacerbated extracellular matrix deposition. However, the role of FAPs in radiation‐induced muscle pathology has not previously been explored.MethodsFour‐week‐old Male CBA or C57Bl/6J mice received a single dose (16 Gy) of irradiation (IR) to a single hindlimb with the shielded contralateral limb (CLTR) serving as a non‐IR control. Mice were sacrificed 3, 7, 14 (acute IR response), and 56 days post‐IR (long‐term IR response). Changes in skeletal muscle morphology, myofibre composition, muscle niche cellular dynamics, DNA damage, proliferation, mitochondrial respiration, and metabolism and changes in progenitor cell fate where assessed.ResultsJuvenile radiation exposure resulted in smaller myofibre cross‐sectional area, particularly in type I and IIA myofibres (P < 0.05) and reduced the proportion of type I myofibres (P < 0.05). Skeletal muscle fibrosis (P < 0.05) was evident at 56 days post‐IR. The IR‐limb had fewer endothelial cells (P < 0.05) and fibro‐adipogenic progenitors (FAPs) (P < 0.05) at 56 days post‐IR. Fewer muscle satellite (stem) cells were detected at 3 and 56 days in the IR‐limb (P < 0.05). IR induced FAP senescence (P < 0.05), increased their fibrogenic differentiation (P < 0.01), and promoted their glycolytic metabolism. Further, IR altered the FAP secretome in a manner that impaired muscle satellite (stem) cell differentiation (P < 0.05) and fusion (P < 0.05).ConclusionsOur study suggests that following juvenile radiation exposure, FAPs contribute to long‐term skeletal muscle atrophy and fibrosis. These findings provide rationale for investigating FAP‐targeted therapies to ameliorate the negative late effects of radiation exposure in skeletal muscle.

Dynamic equilibrium of skeletal muscle macrophage ontogeny in the diaphragm during homeostasis, injury, and recovery

“…However, an important limitation and confounding factor associated with traditional chimeric mouse models is that whole body irradiation leads to impaired skeletal muscle growth and repair 13 , 14 . This has been largely attributed to radiation-induced damage to myogenic precursor (satellite) cells and fibro/adipogenic precursors (FAPs), both of which are required for successful muscle regeneration 15 – 17 . In contrast, there has been little study of the effects of whole body irradiation on resident macrophages in the muscle or whether this intervention alters the balance between bone marrow (monocyte)-dependent and bone marrow-independent macrophages.…”