Helmholtz Gemeinschaft

Search
Browse
Statistics
Feeds

Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation

[thumbnail of Original article]
Preview
PDF (Original article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
4MB

Item Type:Article
Title:Small molecules dorsomorphin and LDN-193189 inhibit myostatin/GDF8 signaling and promote functional myoblast differentiation
Creators Name:Horbelt, D., Boergermann, J.H., Chaikuad, A., Alfano, I., Williams, E., Lukonin, I., Timmel, T., Bullock, A.N. and Knaus, P.
Abstract:GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors Dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the type BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin, and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescue myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis.
Keywords:GDF8, Myostatin, ActRII, Dorsomorphin, LDN-193189, Myogenesis, Animals, Mice, Spodoptera
Source:Journal of Biological Chemistry
ISSN:0021-9258
Publisher:American Society for Biochemistry and Molecular Biology
Volume:290
Number:6
Page Range:3390-3404
Date:6 February 2015
Official Publication:https://doi.org/10.1074/jbc.M114.604397
PubMed:View item in PubMed

Repository Staff Only: item control page

Downloads

Downloads per month over past year

Open Access
MDC Library