Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice.
Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice.
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DOI：
10.3390/biomedicines10102629
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发表时间：
2022-10-19
期刊：
影响因子：
4.7
通讯作者：
Suarez-Calvet, Xavier
中科院分区：
文献类型：
--
作者：
Alonso-Perez, Jorge;Carrasco-Rozas, Ana;Borrell-Pages, Maria;Fernandez-Simon, Esther;Pinol-Jurado, Patricia;Badimon, Lina;Wollin, Lutz;Lleixa, Cinta;Gallardo, Eduard;Olive, Montse;Diaz-Manera, Jordi;Suarez-Calvet, Xavier
肌聚糖病是一组隐性肢带型肌营养不良症，其特征在于进行性肌无力。肌聚糖缺乏在肌肉收缩期间产生肌膜的不稳定性，导致连续的肌纤维损伤，最终产生纤维损失并被纤维脂肪组织替代。旨在减少纤维脂肪扩张的治疗策略可能对肌营养不良症有效。我们报告了尼达尼布在α-肌聚糖病小鼠模型中的积极作用。我们对14只6周龄Sgca-/-小鼠给予尼达尼布50 mg/kg，每12 h给药一次，持续10周，并将肌肉功能和组织学与给予溶剂的14只Sgca-/-小鼠和6只野生型同窝小鼠进行比较。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价。使用常规染色和免疫荧光进行肌肉的结构分析，包括纤维化和炎症过程的详细研究。此外，还进行了蛋白质组学和转录组学研究。尽管我们观察到体重减轻，但给药动物对若虫的耐受性良好。与未给药的Sgca-/-小鼠相比，尼达尼布给药的Sgca-/-小鼠在跑步机上跑的距离更长，并且在抓握试验中显示出更高的力量。此外，尼达尼布改善了给药小鼠的肌肉结构，减少了与细胞因子表达谱逆转相关的退行性区域和纤维化反应。通过减少肌肉纤维化和变性以及恢复慢性炎症环境，Nestrin改善了肌肉功能和肌肉结构，这表明它可能是α-肌聚糖病患者的有用疗法。
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.
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影响因子：
5.8
作者：
Hostettler KE;Zhong J;Papakonstantinou E;Karakiulakis G;Tamm M;Seidel P;Sun Q;Mandal J;Lardinois D;Lambers C;Roth M
通讯作者：
Roth M
影响因子：
14.5
作者：
Alonso-Perez, Jorge;Gonzalez-Quereda, Lidia;Diaz-Manera, Jordi
通讯作者：
Diaz-Manera, Jordi
影响因子：
4.2
作者：
Griffin DA;Pozsgai ER;Heller KN;Potter RA;Peterson EL;Rodino-Klapac LR
通讯作者：
Rodino-Klapac LR
影响因子：
4.8
作者：
Huang, Ping;Zhao, Xinyu S.;Zhou, Lan
通讯作者：
Zhou, Lan
影响因子：
27.4
作者：
Huang, Jingang;Maier, Christiane;Distler, Joerg H. W.
通讯作者：
Distler, Joerg H. W.