Journal Article

Nintedanib decreases muscle fibrosis and improves muscle function in a murine model of dystrophinopathy

Gómez-Gálvez, Pedro, Illa, Isabel, Gallardo, Eduard, Martínez-Muriana, Anna, Suárez-Calvet, Xavier, de la Oliva, Natalia, Wollin, Lutz, Navarro, Xavier, Fernández-Simón, Esther, Díaz-Manera, Jordi, de Luna, Noemi, Piñol-Jurado, Patricia, Pérez-Peiró, María, Escudero, Luis M.

2018

Overview

Duchenne muscle dystrophy (DMD) is a genetic disorder characterized by progressive skeletal muscle weakness. Dystrophin deficiency induces instability of the sarcolemma during muscle contraction that leads to muscle necrosis and replacement of muscle by fibro-adipose tissue. Several therapies have been developed to counteract the fibrotic process. We report the effects of nintedanib, a tyrosine kinase inhibitor, in the mdx murine model of DMD. Nintedanib reduced proliferation and migration of human fibroblasts in vitro and decreased the expression of fibrotic genes such as COL1A1 , COL3A1 , FN1 , TGFB1, and PDGFA . We treated seven mdx mice with 60 mg/kg/day nintedanib for 1 month. Electrophysiological studies showed an increase in the amplitude of the motor action potentials and an improvement of the morphology of motor unit potentials in the animals treated. Histological studies demonstrated a significant reduction of the fibrotic areas present in the skeletal muscles. Analysis of mRNA expression from muscles of treated mice showed a reduction in Col1a1 , Col3a1 , Tgfb1 , and Pdgfa . Western blot showed a reduction in the expression of collagen I in skeletal muscles. In conclusion, nintedanib reduced the fibrotic process in a murine model of dystrophinopathy after 1 month of treatment, suggesting its potential use as a therapeutic drug in DMD patients.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13/1 / 13/106 / 14/1 / 14/19 / 14/34 / 38/77 / 38/90 / 64/60 / 82/1 / 82/80 / Adipose tissue / Animal models / Antibodies / Biochemistry / Biomedical and Life Sciences / Cell Biology / Cell Culture / Collagen (type I) / Dystrophin / Dystrophy / Enzyme inhibitors / Fibroblasts / Fibrosis / Gene expression / Genetic disorders / Immunology / Life Sciences / Migration / Muscle contraction / Protein-tyrosine kinase / Rodents / Sarcolemma / Skeletal muscle / Transforming growth factor-b1