title: Myoferlin regulation by NFAT in muscle injury, regeneration and repair.
abstract: Ferlin proteins mediate membrane-fusion events in response to Ca(2+). Myoferlin, a member of the ferlin family, is required for normal muscle development, during which it mediates myoblast fusion. We isolated both damaged and intact myofibers from a mouse model of muscular dystrophy using laser-capture microdissection and found that the levels of myoferlin mRNA and protein were increased in damaged myofibers. To better define the components of the muscle-injury response, we identified a discreet 1543-bp fragment of the myoferlin promoter, containing multiple NFAT-binding sites, and found that this was sufficient to drive high-level myoferlin expression in cells and in vivo. This promoter recapitulated normal myoferlin expression in that it was downregulated in healthy myofibers and was upregulated in response to myofiber damage. Transgenic mice expressing GFP under the control of the myoferlin promoter were generated and GFP expression in this model was used to track muscle damage in vivo after muscle injury and in muscle disease. Myoferlin modulates the response to muscle injury through its activity in both myoblasts and mature myofibers.
authors.affiliation: Committee on Developmental Biology, The University of Chicago, 5841 South Maryland Avenue, MC 6088, Chicago, IL 60637, USA.
authors.forename: Alexis R
authors.initials: AR
authors.lastname: Demonbreun
authors.forename: Karen A
authors.initials: KA
authors.lastname: Lapidos
authors.forename: Konstantina
authors.initials: K
authors.lastname: Heretis
authors.forename: Samantha
authors.initials: S
authors.lastname: Levin
authors.forename: Rodney
authors.initials: R
authors.lastname: Dale
authors.forename: Peter
authors.initials: P
authors.lastname: Pytel
authors.forename: Eric C
authors.initials: EC
authors.lastname: Svensson
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: McNally
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics; D054715:Cardiotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D023421:Models, Animal; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000254:growth & development / Q000293:injuries / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000032:analysis*; D012038:Regeneration
chemical_list: D054715:Cardiotoxins; D008565:Membrane Proteins; D009124:Muscle Proteins; D050778:NFATC Transcription Factors; D012333:RNA, Messenger; C521810:myoferlin protein, mouse