Facioscapulohumeral muscular dystrophy region gene 1 over-expression causes primary defects of myogenic stem cells.

Journal of Cell Science (Impact Factor: 5.43). 03/2013; 126(10). DOI: 10.1242/jcs.121533
Source: PubMed


Over-expression of FSHD Region Gene 1 (FRG1) in mice, frogs and worms leads to muscular and vascular abnormalities. Nevertheless, the mechanism that follows FRG1 over-expression and finally leads to muscular defects is currently unknown. Here, we show that the earliest phenotype displayed by FRG1 mice is a postnatal muscle-growth defect. Long before the development of muscular dystrophy, FRG1 mice exhibit also a muscle regeneration impairment. Ex-vivo and in-vivo experiments revealed that FRG1 over-expression causes myogenic stem-cell activation, proliferative, clonogenic and differentiation defects. A comparative gene expression profiling of WT and FRG1 muscles from young pre-dystrophic mice identified differentially expressed genes in several gene categories and networks that could explain the emerging tissue and myogenic stem-cell defects. Overall, our study provides new insights in the pathways regulated by FRG1 and suggests that muscle-stem cells defects could contribute to the pathology of FRG1 mice.

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    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is characterized by atrophy and weakness of selective muscle groups. FSHD is considered an autosomal dominant disease with incomplete penetrance and unpredictable variability of clinical expression within families. Mice over-expressing FRG1 (FSHD region gene 1), a candidate gene for this disease, develop a progressive myopathy with features of the human disorder. Here we show that in FRG1 over-expressing mice, fast muscles, which are the most affected by the dystrophic process, display anomalous fast skeletal troponin T (fTnT) isoform resulting from the aberrant splicing of the Tnnt3 mRNA that precedes the appearance of dystrophic signs. We determine that muscles of FRG1 mice develop less strength due to impaired contractile properties of fast-twitch fibers associated with an anomalous MyHC/actin ratio and a reduced sensitivity to Ca2+. We demonstrate that the decrease of Ca2+ sensitivity of fast-twitch fibers depends on the anomalous troponin complex and can be rescued by the substitution with the wild-type proteins. Finally, we find that the presence of aberrant splicing isoforms of TNNT3 characterizes dystrophic muscles in FSHD patients. Collectively, our results suggest that anomalous TNNT3 profile correlates with the muscle impairment in both humans and mice. On the basis of these results, we propose that aberrant fTnT represents a biological marker of muscle phenotype severity and disease progression.
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    Mechanisms of Development 09/2014; 134. DOI:10.1016/j.mod.2014.08.003 · 2.44 Impact Factor
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    ABSTRACT: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders. The major form of the disease (FSHD1) is linked to decrease in copy number of a 3.3-kb tandem repeated macrosatellite (D4Z4), located on chromosome 4q35. D4Z4 deletion alters chromatin structure of the locus leading to aberrant expression of nearby 4q35 genes. Given the high variability in disease onset and progression, multiple factors could contribute to the pathogenesis of FSHD. Among the FSHD candidate genes are DUX4 (double homeobox 4), encoded by the most telomeric D4Z4 unit, and FRG1 (FSHD region gene 1). DUX4 is a sequence-specific transcription factor. Here, we located putative DUX4 binding sites in the human FRG1 genomic area and we show specific DUX4 association to these regions. We found also that ectopically expressed DUX4 up-regulates the endogenous human FRG1 gene in healthy muscle cells, while DUX4 knockdown leads to a decrease in FRG1 expression in FSHD muscle cells. Moreover, DUX4 binds directly and specifically to its binding site located in the human FRG1 gene and transactivates constructs containing FRG1 genomic regions. Intriguingly, the mouse Frg1 genomic area lacks DUX4 binding sites and DUX4 is unable to activate the endogenous mouse Frg1 gene providing a possible explanation for the lack of muscle phenotype in DUX4 transgenic mice. Altogether, our results demonstrate that FRG1 is a direct DUX4 transcriptional target uncovering a novel regulatory circuit contributing to FSHD.
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