NOX4 inhibition reduces skeletal muscle fibrosis in a severe murine model of Duchenne muscular dystrophy


Pre-Clinical Research

Poster Number: 18


David Hammers Ph.D.


1. University of Florida

The muscular dystrophies (MDs) are a class of genetic muscle diseases often characterized by progressive degeneration and replacement of muscle with fibrotic tissue. Limited treatment options exist for MD patients, and no therapeutics specifically target the progression of intramuscular fibrosis. NAD(P)H oxidase (NOX) 4 has been previously implicated in the development of fibrosis in other organs, but not skeletal muscle. The specific aim of the current report was to investigate NOX4 as a potential anti-fibrotic target in dystrophic skeletal muscle, using the severe D2.mdx mouse model of Duchenne muscular dystrophy (DMD). It is shown that NOX4 is increased in the muscles of D2.mdx mice and localizes primarily to interstitial regions between muscle fibers. In agreement with the hypothesis that this increase in NOX4 contributes to muscle fibrosis, genetic ablation of Nox4 prevents the progressive accumulation of fibrosis in skeletal muscle. Furthermore, it is demonstrated that pharmacological targeting of NOX4 using the small molecule clinical candidate NOX1/4 inhibitor, GKT137831, also prevents the progression of intramuscular fibrosis in the diaphragm and gastrocnemius of D2.mdx mice. Mechanistically, NOX4 loss-of-function results in decreased accumulation of periostin and periostin-associated interstitial cells within dystrophic muscle. These data indicate NOX4 is an effective anti-fibrotic target to combat progression of intramuscular fibrosis in DMD and, potentially, other MDs.