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Article

Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy

1
Department of Animal Sciences, The Hebrew University of Jerusalem, P.O. Box 12, Rehovot 76100, Israel
2
Center for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, D04 N2E5 Dublin, Ireland
3
The Volcani Center, Institute of Animal Science, Bet Dagan 52505, Israel
*
Author to whom correspondence should be addressed.
Academic Editor: Jeffrey Glennon
Int. J. Mol. Sci. 2021, 22(13), 7063; https://doi.org/10.3390/ijms22137063
Received: 25 May 2021 / Revised: 25 June 2021 / Accepted: 29 June 2021 / Published: 30 June 2021
(This article belongs to the Special Issue Molecular Mechanisms of Muscular Dystrophy)
Progressive loss of muscle and muscle function is associated with significant fibrosis in Duchenne muscular dystrophy (DMD) patients. Halofuginone, an analog of febrifugine, prevents fibrosis in various animal models, including those of muscular dystrophies. Effects of (+)/(−)-halofuginone enantiomers on motor coordination and diaphragm histopathology in mdx mice, the mouse model for DMD, were examined. Four-week-old male mice were treated with racemic halofuginone, or its separate enantiomers, for 10 weeks. Controls were treated with saline. Racemic halofuginone-treated mice demonstrated better motor coordination and balance than controls. However, (+)-halofuginone surpassed the racemic form’s effect. No effect was observed for (−)-halofuginone, which behaved like the control. A significant reduction in collagen content and degenerative areas, and an increase in utrophin levels were observed in diaphragms of mice treated with racemic halofuginone. Again, (+)-halofuginone was more effective than the racemic form, whereas (−)-halofuginone had no effect. Both racemic and (+)-halofuginone increased diaphragm myofiber diameters, with no effect for (−)-halofuginone. No effects were observed for any of the compounds tested in an in-vitro cell viability assay. These results, demonstrating a differential effect of the halofuginone enantiomers and superiority of (+)-halofuginone, are of great importance for future use of (+)-halofuginone as a DMD antifibrotic therapy. View Full-Text
Keywords: skeletal muscle; Duchenne muscular dystrophy; fibrosis; utrophin; halofuginone; stereoisomer; febrifugine skeletal muscle; Duchenne muscular dystrophy; fibrosis; utrophin; halofuginone; stereoisomer; febrifugine
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MDPI and ACS Style

Mordechay, S.; Smullen, S.; Evans, P.; Genin, O.; Pines, M.; Halevy, O. Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy. Int. J. Mol. Sci. 2021, 22, 7063. https://doi.org/10.3390/ijms22137063

AMA Style

Mordechay S, Smullen S, Evans P, Genin O, Pines M, Halevy O. Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy. International Journal of Molecular Sciences. 2021; 22(13):7063. https://doi.org/10.3390/ijms22137063

Chicago/Turabian Style

Mordechay, Sharon, Shaun Smullen, Paul Evans, Olga Genin, Mark Pines, and Orna Halevy. 2021. "Differential Effects of Halofuginone Enantiomers on Muscle Fibrosis and Histopathology in Duchenne Muscular Dystrophy" International Journal of Molecular Sciences 22, no. 13: 7063. https://doi.org/10.3390/ijms22137063

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