Searching across hundreds of databases

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Dystrophic muscle improvement in zebrafish via increased heme oxygenase signaling.

Human molecular genetics | Apr 1, 2014

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 mdx(5cv) 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.

Pubmed ID: 24234649 RIS Download

Mesh terms: Animals | Cyclic GMP | Cyclic Nucleotide Phosphodiesterases, Type 5 | Disease Models, Animal | Drug Evaluation, Preclinical | Dystrophin | Heme Oxygenase-1 | Mice | Mice, Inbred C57BL | Mice, Transgenic | Muscular Dystrophy, Duchenne | Phosphodiesterase 5 Inhibitors | Piperazines | Purines | RNA, Messenger | Signal Transduction | Sildenafil Citrate | Sulfones | Up-Regulation | Zebrafish

Research resources used in this publication

None found

Research tools detected in this publication

None found

Data used in this publication

None found

Associated grants

  • Agency: NICHD NIH HHS, Id: 2P30HD018655-30
  • Agency: NINDS NIH HHS, Id: 5P50NS040828-10
  • Agency: NICHD NIH HHS, Id: P30-HD-18655

ZFIN (Data, Gene Expression)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

We have not found any resources mentioned in this publication.