title: Halofuginone promotes satellite cell activation and survival in muscular dystrophies.
abstract: 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.
authors.affiliation: Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Hila
authors.initials: H
authors.lastname: Barzilai-Tutsch
authors.affiliation: Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Bodanovsky
authors.affiliation: Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Maimon
authors.affiliation: Institute of Animal Science, The Volcani Center, Bet Dagan 52505, Israel.
authors.forename: Mark
authors.initials: M
authors.lastname: Pines
authors.affiliation: Department of Animal Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Electronic address: orna.halevy@mail.huji.ac.il.
authors.forename: Orna
authors.initials: O
authors.lastname: Halevy
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use*; D032496:Satellite Cells, Skeletal Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D010880:Piperidines; D052999:Quinazolinones; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C010176:halofuginone
keywords: Apoptosis; Cell cycle; Halofuginone; Muscular dystrophy; Myofiber; Satellite cell