4.7 Article

Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice

期刊

BIOMEDICINES
卷 10, 期 10, 页码 -

出版社

MDPI
DOI: 10.3390/biomedicines10102629

关键词

sarcoglycanopathy; Sgca; muscular dystrophy; fibrosis; nintedanib; mice

资金

  1. Spanish Ministry of Health, Fondos FEDER-ISCIII [PI18/01525]
  2. Academy of Medical Sciences Professorship Scheme [APR4/1007]
  3. MRC [MR/W019086/1]
  4. Rio Hortega grant [CM19/00178]
  5. Accion Estrategica de Salud (EAS)
  6. Instituto de Salud Carlos III (Spain)
  7. ERDF/ESF, investing in your future
  8. Instituto de Salud Carlos III (Sara Borrell fellowship) [CD18/00195]
  9. European Regional Development Fund (ERDF)/European Social Fund (ESF), investing in your future
  10. Instituto de Salud Carlos III [FIS2020-01282]
  11. Boehringer Ingelheim, Ingelheim, Germany

向作者/读者索取更多资源

This study found that nintedanib has a positive effect on a murine model of alpha-sarcoglycanopathy. Nintedanib can improve muscle function and architecture by reducing muscle fibrosis and degeneration and reverting the chronic inflammatory environment.
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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