PDF(Pubmed)
Abstract：
Sarcoglycanopathies are a group of recessive limb-girdle muscular dystrophies, characterized by progressive muscle weakness. Sarcoglycan deficiency produces instability of the sarcolemma during muscle contraction, leading to continuous muscle fiber injury eventually producing fiber loss and replacement by fibro-adipose tissue. Therapeutic strategies aiming to reduce fibro-adipose expansion could be effective in muscular dystrophies. We report the positive effect of nintedanib in a murine model of alpha-sarcoglycanopathy. We treated 14 Sgca-/- mice, six weeks old, with nintedanib 50 mg/kg every 12 h for 10 weeks and compared muscle function and histology with 14 Sgca-/- mice treated with vehicle and six wild-type littermate mice. Muscle function was assessed using a treadmill and grip strength. A cardiac evaluation was performed by echocardiography and histological study. Structural analysis of the muscles, including a detailed study of the fibrotic and inflammatory processes, was performed using conventional staining and immunofluorescence. In addition, proteomics and transcriptomics studies were carried out. Nintedanib was well tolerated by the animals treated, although we observed weight loss. Sgca-/- mice treated with nintedanib covered a longer distance on the treadmill, compared with non-treated Sgca-/- mice, and showed higher strength in the grip test. Moreover, nintedanib improved the muscle architecture of treated mice, reducing the degenerative area and the fibrotic reaction that was associated with a reversion of the cytokine expression profile. Nintedanib improved muscle function and muscle architecture by reducing muscle fibrosis and degeneration and reverting the chronic inflammatory environment suggesting that it could be a useful therapy for patients with alpha-sarcoglycanopathy.
摘要：
肌糖病是一组隐性肢带肌营养不良，以进行性肌肉无力为特征。在肌肉收缩过程中，肌球蛋白缺乏会导致肌膜不稳定，导致持续的肌纤维损伤，最终导致纤维丢失和纤维脂肪组织替代。旨在减少纤维脂肪扩张的治疗策略可能对肌营养不良有效。我们报道了尼达尼布在α-肌糖病小鼠模型中的积极作用。我们治疗了14只Sgca-/-小鼠，六周大,每12小时服用尼达尼布50mg/kg，持续10周，并比较了14只Sgca-/-小鼠和6只野生型同窝小鼠的肌肉功能和组织学。使用跑步机和握力评估肌肉功能。通过超声心动图和组织学研究进行心脏评估。肌肉的结构分析，包括对纤维化和炎症过程的详细研究，使用常规染色和免疫荧光进行。此外,进行了蛋白质组学和转录组学研究。Nintedanib被治疗的动物耐受良好，虽然我们观察到体重减轻。用尼达尼布治疗的Sgca-/-小鼠在跑步机上覆盖了更长的距离，与未治疗的Sgca-/-小鼠相比，并在抓地力测试中显示出更高的强度。此外，尼达尼布改善了治疗小鼠的肌肉结构，减少与细胞因子表达谱逆转相关的变性区域和纤维化反应。Nintedanib通过减少肌肉纤维化和变性并恢复慢性炎症环境来改善肌肉功能和肌肉结构，这表明Nintedanib可能是α-肌糖病患者的有用疗法。
