title: FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1).
abstract: Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Feeney
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Meagan J
authors.initials: MJ
authors.lastname: McGrath
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Absorn
authors.initials: A
authors.lastname: Sriratana
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Gehrig
authors.affiliation: Basic and Clinical Myology Laboratory, Department of Physiology, The University of Melbourne, Victoria, 3010, Australia.
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Lynch
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: D'Arcy
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia; Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne, Victoria, 8001, Australia.
authors.forename: John T
authors.initials: JT
authors.lastname: Price
authors.affiliation: Department of Anatomical Pathology, Alfred Hospital, Prahran, Victoria, 3004, Australia; Department of Medicine, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia.
authors.forename: Catriona A
authors.initials: CA
authors.lastname: McLean
authors.affiliation: Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA, 01655, United States of America; Dipartimento di Scienze della Vita, Universita di Modena e Reggio Emilia, 41125, Modena, Italy.
authors.forename: Rossella
authors.initials: R
authors.lastname: Tupler
authors.affiliation: Department of Biochemistry & Molecular Biology, Monash University, Clayton, Victoria, 3800, Australia.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D002460:Cell Line; D005260:Female; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D024510:Muscle Development / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology / Q000503:physiopathology; D020391:Muscular Dystrophy, Facioscapulohumeral / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins
chemical_list: C101149:FHL1 protein, human; C101270:FRG1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D009124:Muscle Proteins; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins