Program in Gene Function and Expression; Department of Molecular, Cell and Cancer Biology
Cell and Developmental Biology | Cellular and Molecular Physiology | Molecular Biology | Molecular Genetics | Musculoskeletal Diseases | Nervous System Diseases
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.
Facioscapulohumeral muscular dystrophy (FSHD), FRG1, FHL1
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Copyright: © 2015 Feeney et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
DOI of Published Version
PLoS One. 2015 Feb 19;10(2):e0117665. doi: 10.1371/journal.pone.0117665. Link to article on publisher's site
Feeney SJ, McGrath MJ, Sriratana A, Gehrig SM, Lynch GS, D'Arcy CE, Price JT, McLean CA, Tupler RG, Mitchell CA. (2015). FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1). Open Access Articles. https://doi.org/10.1371/journal.pone.0117665. Retrieved from https://escholarship.umassmed.edu/oapubs/2480
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