Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 35 Convent Drive, BLDG 35 RM 2A116, Bethesda, Maryland, 20892, USA.
Bioinformatics Section, Intramural Information Technology & Bioinformatics Program, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, BG 10 RM 5S223, Bethesda, Maryland, 20892, USA.
Ann Clin Transl Neurol. 2021 Nov;8(11):2184-2198. doi: 10.1002/acn3.51450. Epub 2021 Nov 2.
To define the transcriptomic changes responsible for the histologic alterations in skeletal muscle and their progression in collagen VI-related muscular dystrophy (COL6-RD).
COL6-RD patient muscle biopsies were stratified into three groups based on the overall level of pathologic severity considering degrees of fibrosis, muscle fiber atrophy, and fatty replacement of muscle tissue. Using microarray and RNA-Seq, we then performed global gene expression profiling on the same muscle biopsies and compared their transcriptome with age- and sex-matched controls.
COL6-RD muscle biopsy transcriptomes as a group revealed prominent upregulation of muscle extracellular matrix component genes and the downregulation of skeletal muscle and mitochondrion-specific genes. Upregulation of the TGFβ pathway was the most conspicuous change across all biopsies and was fully evident even in the mildest/earliest histological group. There was no difference in the overall transcriptional signature between the different histologic groups but polyserial analysis identified relative changes along with COL6-RD histological severity.
Overall, our study establishes the prominent dysregulation of extracellular matrix genes, TGFβ signaling, and its downstream cellular pathways at the transcriptomic level in COL6-RD muscle.
确定导致骨骼肌肉组织学改变的转录组变化及其在胶原 VI 相关肌营养不良症（COL6-RD）中的进展。
根据纤维化、肌肉纤维萎缩和肌肉组织脂肪替代的程度，对 COL6-RD 患者的肌肉活检进行分组，基于整体病理严重程度分为三组。然后，我们使用微阵列和 RNA-Seq 对相同的肌肉活检进行了全基因表达谱分析，并将其转录组与年龄和性别匹配的对照组进行了比较。
COL6-RD 肌肉活检转录组作为一个整体，显示肌肉细胞外基质成分基因的显著上调和骨骼肌和线粒体特异性基因的下调。TGFβ 通路的上调是所有活检中最明显的变化，即使在最轻微/最早的组织学组中也完全明显。不同组织学组之间的整体转录特征没有差异，但多序列分析确定了与 COL6-RD 组织学严重程度相关的相对变化。
总的来说，我们的研究在 COL6-RD 肌肉的转录组水平上确立了细胞外基质基因、TGFβ 信号及其下游细胞途径的明显失调。
