Ferreboeuf Maxime, Mariot Virginie, Bessières Bettina, Vasiljevic Alexandre, Attié-Bitach Tania, Collardeau Sophie, Morere Julia, Roche Stéphane, Magdinier Frédérique, Robin-Ducellier Jérôme, Rameau Philippe, Whalen Sandra, Desnuelle Claude, Sacconi Sabrina, Mouly Vincent, Butler-Browne Gillian, Dumonceaux Julie
INSERM U974, UMR 7215 CNRS, Institut de Myologie, UM 76 Université Pierre et Marie Curie, Paris 75013, France.
Hum Mol Genet. 2014 Jan 1;23(1):171-81. doi: 10.1093/hmg/ddt409. Epub 2013 Aug 20.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent adult muscular dystrophies. The common clinical signs usually appear during the second decade of life but when the first molecular dysregulations occur is still unknown. Our aim was to determine whether molecular dysregulations can be identified during FSHD fetal muscle development. We compared muscle biopsies derived from FSHD1 fetuses and the cells derived from some of these biopsies with biopsies and cells derived from control fetuses. We mainly focus on DUX4 isoform expression because the expression of DUX4 has been confirmed in both FSHD cells and biopsies by several laboratories. We measured DUX4 isoform expression by using qRT-PCR in fetal FSHD1 myotubes treated or not with an shRNA directed against DUX4 mRNA. We also analyzed DUX4 downstream target gene expression in myotubes and fetal or adult FSHD1 and control quadriceps biopsies. We show that both DUX4-FL isoforms are already expressed in FSHD1 myotubes. Interestingly, DUX4-FL expression level is much lower in trapezius than in quadriceps myotubes, which is confirmed by the level of expression of DUX4 downstream genes. We observed that TRIM43 and MBD3L2 are already overexpressed in FSHD1 fetal quadriceps biopsies, at similar levels to those observed in adult FSHD1 quadriceps biopsies. These results indicate that molecular markers of the disease are already expressed during fetal life, thus opening a new field of investigation for mechanisms leading to FSHD.
面肩肱型肌营养不良症（FSHD）是最常见的成人肌营养不良症之一。常见的临床症状通常在生命的第二个十年出现，但首次分子失调发生的时间仍不清楚。我们的目的是确定在FSHD胎儿肌肉发育过程中是否可以识别出分子失调。我们将来自FSHD1胎儿的肌肉活检样本以及其中一些活检样本衍生的细胞与来自对照胎儿的活检样本和细胞进行了比较。我们主要关注DUX4异构体的表达，因为几个实验室已在FSHD细胞和活检样本中证实了DUX4的表达。我们通过qRT-PCR测量了用针对DUX4 mRNA的shRNA处理或未处理的胎儿FSHD1肌管中DUX4异构体的表达。我们还分析了肌管以及胎儿或成人FSHD1和对照股四头肌活检样本中DUX4下游靶基因的表达。我们发现DUX4-FL两种异构体在FSHD1肌管中均已表达。有趣的是，斜方肌中DUX4-FL的表达水平远低于股四头肌肌管中的表达水平，这一点通过DUX4下游基因的表达水平得到了证实。我们观察到TRIM43和MBD3L2在FSHD1胎儿股四头肌活检样本中已经过表达，其水平与在成人FSHD1股四头肌活检样本中观察到的水平相似。这些结果表明该疾病的分子标志物在胎儿期就已经表达，从而为导致FSHD的机制开辟了一个新的研究领域。
