Duchenne muscular dystrophy (DMD) is caused by a lack of the dystrophin protein and has no effective treatment at present.
Zebrafish provide a powerful in vivo tool for high-throughput therapeutic drug screening for the improvement of muscle phenotypes caused by dystrophin deficiency.
Using the dystrophin-deficient zebrafish, sapje, we have screened a total of 2640 compounds with known modes of action from three drug libraries to identify modulators of
the disease progression. Six compounds that target heme oxygenase signaling were found to rescue the abnormal muscle phenotype
in sapje and sapje-like, while upregulating the inducible heme oxygenase 1 (Hmox1) at the protein level. Direct Hmox1 overexpression by injection
of zebrafish Hmox1 mRNA into fertilized eggs was found to be sufficient for a dystrophin-independent restoration of normal
muscle via an upregulation of cGMP levels. In addition, treatment of mdx5cv mice with the PDE5 inhibitor, sildenafil, which was one of the six drugs impacting the Hmox1 pathway in zebrafish, significantly
increased the expression of Hmox1 protein, thus making Hmox1 a novel target for the improvement of dystrophic symptoms. These
results demonstrate the translational relevance of our zebrafish model to mammalian models and support the use of zebrafish
to screen for new drugs to treat human DMD. The discovery of a small molecule and a specific therapeutic pathway that might
mitigate DMD disease progression could lead to significant clinical implications.