Halofuginone promotes satellite cell activation and survival in muscular dystrophies.
Halofuginone is a leading agent in preventing fibrosis and inflammation in various muscular dystrophies. We hypothesized that in addition to these actions, halofuginone directly promotes the cell-cycle events of satellite cells in the mdx and dysf(-/-) mouse models of early-onset Duchenne muscular dystrophy and late-onset dysferlinopathy, respectively. In both models, addition of halofuginone to freshly prepared single gastrocnemius myofibers derived from 6-week-old mice increased BrdU incorporation at as early as 18h of incubation, as well as phospho-histone H3 (PHH3) and MyoD protein expression in the attached satellite cells, while having no apparent effect on myofibers derived from wild-type mice. BrdU incorporation was abolished by an inhibitor of mitogen-activated protein kinase/extracellular signal-regulated protein kinase, suggesting involvement of this pathway in mediating halofuginone's effects on cell-cycle events. In cultures of myofibers and myoblasts isolated from dysf(-/-) mice, halofuginone reduced Bax and induced Bcl2 expression levels and induced Akt phosphorylation in a time-dependent manner. Addition of an inhibitor of the phosphinositide-3-kinase/Akt pathway reversed the halofuginone-induced cell survival, suggesting this pathway's involvement in mediating halofuginone's effects on survival. Thus, in addition to its known role in inhibiting fibrosis and inflammation, halofuginone plays a direct role in satellite cell activity and survival in muscular dystrophies, regardless of the mutation. These actions are of the utmost importance for improving muscle pathology and function in muscular dystrophies.
['Barzilai-Tutsch|Hila|H|', 'Bodanovsky|Anna|A|', 'Maimon|Hadar|H|', 'Pines|Mark|M|', 'Halevy|Orna|O|']
D000818:Animals D017209:Apoptosis D002453:Cell Cycle D002470:Cell Survival D020935:MAP Kinase Signaling System D008297:Male D051379:Mice D008810:Mice, Inbred C57BL D018485:Muscle Fibers, Skeletal D049288:Muscular Dystrophies, Limb-Girdle D020388:Muscular Dystrophy, Duchenne D019869:Phosphatidylinositol 3-Kinases D010880:Piperidines D051057:Proto-Oncogene Proteins c-akt D052999:Quinazolinones D032496:Satellite Cells, Skeletal Muscle D015398:Signal Transduction
Halofuginone Satellite cell Muscular dystrophy Myofiber Apoptosis Cell cycle