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

Cell Death Dis. 2018 Jul 10;9(7):776. doi: 10.1038/s41419-018-0792-6.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Animals
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III / metabolism
  • Disease Models, Animal
  • Dystrophin / metabolism
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Indoles / therapeutic use*
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle Weakness / drug therapy
  • Muscle Weakness / metabolism
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • Muscular Dystrophy, Duchenne / drug therapy*
  • Muscular Dystrophy, Duchenne / metabolism
  • Platelet-Derived Growth Factor / metabolism
  • Transforming Growth Factor beta1 / metabolism


  • COL3A1 protein, mouse
  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Collagen Type III
  • Dystrophin
  • Indoles
  • Platelet-Derived Growth Factor
  • Tgfb1 protein, mouse
  • Transforming Growth Factor beta1
  • platelet-derived growth factor A
  • nintedanib