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

Medienart:

E-Artikel

Erscheinungsjahr:

2021

Erschienen:

2021

Enthalten in:

Zur Gesamtaufnahme - volume:22

Enthalten in:

International journal of molecular sciences - 22(2021), 13 vom: 30. Juni

Sprache:

Englisch

Beteiligte Personen:

Mordechay, Sharon [VerfasserIn]
Smullen, Shaun [VerfasserIn]
Evans, Paul [VerfasserIn]
Genin, Olga [VerfasserIn]
Pines, Mark [VerfasserIn]
Halevy, Orna [VerfasserIn]

Links:

Volltext

Themen:

Duchenne muscular dystrophy
Febrifugine
Fibrosis
Halofuginone
Journal Article
L31MM1385E
Piperidines
Quinazolinones
Skeletal muscle
Stereoisomer
Utrophin

Anmerkungen:

Date Completed 21.07.2021

Date Revised 21.07.2021

published: Electronic

Citation Status MEDLINE

doi:

10.3390/ijms22137063

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM327558342