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

IF 8.9 1区 医学 Journal of Cachexia, Sarcopenia and Muscle Pub Date : 2023-09-06 DOI:10.1002/jcsm.13320
Nicolas Collao, Donna D'Souza, Laura Messeiller, Evan Pilon, Jessica Lloyd, Jillian Larkin, Matthew Ngu, Alexanne Cuillerier, Alexander E. Green, Keir J. Menzies, Yan Burelle, Michael De Lisio
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Abstract

Background

Radiation-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.

Methods

Four-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.

Results

Juvenile 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).

Conclusions

Our 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.

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辐射诱导长期肌肉纤维化,并促进纤维脂肪生成祖细胞的纤维化表型。
背景:辐射诱导的肌肉病理以肌肉萎缩和纤维组织积聚为特征,是治疗性辐射暴露最常见的晚期衰弱效应,尤其是在癌症青年幸存者中。在健康肌肉中,纤维/脂肪生成祖细胞(FAPs)是肌肉维持和再生所必需的,而在肌肉病理学中,FAPs是细胞外基质沉积加剧的前体。然而,FAPs在辐射诱导的肌肉病理中的作用以前还没有被探索过。方法:4周龄雄性CBA或C57Bl/6J小鼠接受单剂量(16Gy)的单后肢照射(IR),对侧肢体(CLTR)作为非IR对照。在IR后3、7、14天(急性IR反应)和56天(长期IR反应)处死小鼠。骨骼肌形态、肌纤维组成、肌肉生态位细胞动力学、DNA损伤、增殖、线粒体呼吸和代谢的变化,以及祖细胞命运的变化。结果:青少年辐射暴露导致肌原纤维截面积变小,特别是在I型和IIA型肌纤维中(P结论:我们的研究表明,在青少年辐射暴露后,FAP会导致长期骨骼肌萎缩和纤维化。这些发现为研究FAP靶向治疗提供了理论依据,以改善辐射暴露对骨骼肌的负性后期影响。
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Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine
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期刊介绍: The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.
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