Almeida Camila F, Martins Poliana Cm, Vainzof Mariz
Laboratory of Muscle Proteins and Comparative Histopathology, Human Genome and Stem Cell Research Center, Department of Genetics and Evolutionary Biology, Biosciences Institute, University of São Paulo, São Paulo, Brazil.
Eur J Hum Genet. 2016 Aug;24(9):1301-9. doi: 10.1038/ejhg.2016.16. Epub 2016 Mar 2.
Muscular dystrophies (MD) are a clinically and genetically heterogeneous group of Mendelian diseases. The underlying pathophysiology and phenotypic variability in each form are much more complex, suggesting the involvement of many other genes. Thus, here we studied the whole genome expression profile in muscles from three mice models for MD, at different time points: Dmd(mdx) (mutation in dystrophin gene), Large(myd-/-) (mutation in Large) and Dmd(mdx)/Large(myd-/-) (both mutations). The identification of altered biological functions can contribute to understand diseases and to find prognostic biomarkers and points for therapeutic intervention. We identified a substantial number of differentially expressed genes (DEGs) in each model, reflecting diseases' complexity. The main biological process affected in the three strains was immune system, accounting for the majority of enriched functional categories, followed by degeneration/regeneration and extracellular matrix remodeling processes. The most notable differences were in 21-day-old Dmd(mdx), with a high proportion of DEGs related to its regenerative capacity. A higher number of positive embryonic myosin heavy chain (eMyHC) fibers confirmed this. The new Dmd(mdx)/Large(myd-/-) model did not show a highly different transcriptome from the parental lineages, with a profile closer to Large(myd-/-), but not bearing the same regenerative potential as Dmd(mdx). This is the first report about transcriptome profile of a mouse model for congenital MD and Dmd(mdx)/Large(myd). By comparing the studied profiles, we conclude that alterations in biological functions due to the dystrophic process are very similar, and that the intense regeneration in Dmd(mdx) involves a large number of activated genes, not differentially expressed in the other two strains.
肌肉萎缩症（MD）是一组临床和遗传异质性的孟德尔疾病。每种类型潜在的病理生理学和表型变异性要复杂得多，这表明还有许多其他基因参与其中。因此，我们在此研究了三种肌肉萎缩症小鼠模型在不同时间点的肌肉全基因组表达谱：Dmd（mdx）（肌营养不良蛋白基因突变）、Large（myd-/-）（Large基因突变）和Dmd（mdx）/Large（myd-/-）（两种突变均有）。确定改变的生物学功能有助于理解疾病，并找到预后生物标志物和治疗干预靶点。我们在每个模型中都鉴定出了大量差异表达基因（DEG），这反映了疾病的复杂性。这三种品系中受影响的主要生物学过程是免疫系统，占富集功能类别的大多数，其次是退化/再生和细胞外基质重塑过程。最显著的差异出现在21日龄的Dmd（mdx）中，其中与再生能力相关的DEG比例很高。更多数量的阳性胚胎肌球蛋白重链（eMyHC）纤维证实了这一点。新的Dmd（mdx）/Large（myd-/-）模型的转录组与亲本品系相比没有显示出高度差异，其图谱更接近Large（myd-/-），但不具备与Dmd（mdx）相同的再生潜力。这是关于先天性肌肉萎缩症小鼠模型Dmd（mdx）/Large（myd）转录组图谱的首次报道。通过比较所研究的图谱，我们得出结论，营养不良过程导致的生物学功能改变非常相似，并且Dmd（mdx）中的强烈再生涉及大量激活基因，而这些基因在其他两个品系中没有差异表达。
