Nintedanib Reduces Muscle Fibrosis and Improves Muscle Function of the Alpha-Sarcoglycan-Deficient Mice
Alonso-Pérez, Jorge (Universitat Autònoma de Barcelona. Departament de Medicina)
Carrasco-Rozas, Ana (Universitat Autònoma de Barcelona. Departament de Medicina)
Borrell-Pages, Maria (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Fernández Simón, Esther (Newcastle University)
Piñol-Jurado, Patricia (Newcastle University)
Badimon, Lina (Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares)
Wollin, Lutz (Boehringer Ingelheim)
Lleixà, Cinta (Universitat Autònoma de Barcelona. Departament de Medicina)
Gallardo, Eduard (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Olive, Montse (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Diaz-Manera, Jordi (Centro de Investigación Biomédica en Red de Enfermedades Raras)
Suárez-Calvet, Xavier (Centro de Investigación Biomédica en Red de Enfermedades Raras)

Data:	2022
Resum:	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.
Ajuts:	Instituto de Salud Carlos III CD18/00195 Instituto de Salud Carlos III FIS2020-01282 Instituto de Salud Carlos III PI18/01525
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Publicat a:	Biomedicines, Vol. 10 Núm. 10 (october 2022) , p. 2629, ISSN 2227-9059

DOI: 10.3390/biomedicines10102629
PMID: 36289891

17 p, 2.7 MB

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