Drug screening in a zebrafish model of Duchenne muscular dystrophy

TLDR

Zebrafish dystrophin mutants sapje and sapje‑like serve as robust small‑animal models for human muscular dystrophy. The authors screened the Prestwick chemical library in dystrophin‑null zebrafish to identify small molecules that modulate muscle pathology. The screen uncovered seven compounds that improved muscle pathology, with three—including the PDE inhibitor aminophylline—restoring normal birefringence, enhancing survival, and activating the cAMP‑PKA pathway, thereby validating the assay and highlighting PDE inhibitors as promising therapeutic leads for muscular dystrophy.

Abstract

Two known zebrafish dystrophin mutants, sapje and sapje -like ( sap c/100 ), represent excellent small-animal models of human muscular dystrophy. Using these dystrophin-null zebrafish, we have screened the Prestwick chemical library for small molecules that modulate the muscle phenotype in these fish. With a quick and easy birefringence assay, we have identified seven small molecules that influence muscle pathology in dystrophin-null zebrafish without restoration of dystrophin expression. Three of seven candidate chemicals restored normal birefringence and increased survival of dystrophin-null fish. One chemical, aminophylline, which is known to be a nonselective phosphodiesterase (PDE) inhibitor, had the greatest ability to restore normal muscle structure and up-regulate the cAMP-dependent PKA pathway in treated dystrophin-deficient fish. Moreover, other PDE inhibitors also reduced the percentage of affected sapje fish. The identification of compounds, especially PDE inhibitors, that moderate the muscle phenotype in these dystrophin-null zebrafish validates the screening protocol described here and may lead to candidate molecules to be used as therapeutic interventions in human muscular dystrophy.