CNR-National Research Council of Italy, Institute of Molecular Genetics-IOR, Bologna, Italy.
Matrix Biol. 2012 Apr;31(3):187-96. doi: 10.1016/j.matbio.2011.12.003. Epub 2011 Dec 30.
Collagen VI is a major extracellular matrix (ECM) protein with a critical role in maintaining skeletal muscle functional integrity. Mutations in COL6A1, COL6A2 and COL6A3 genes cause Ullrich Congenital Muscular Dystrophy (UCMD), Bethlem Myopathy, and Myosclerosis. Moreover, Col6a1(-/-) mice and collagen VI deficient zebrafish display a myopathic phenotype. Recently, two additional collagen VI chains were identified in humans, the α5 and α6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the α6 chain was detected in the endomysium and perimysium, while the α5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the α6 chain was present in traces in the ECM, while the α5 chain was not detected. In the absence of ascorbic acid, the α6 chain was mainly accumulated into the cytoplasm of a sub-set of desmin negative cells, likely of interstitial origin, which can be considered myofibroblasts as they expressed α-smooth muscle actin. TGF-β1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the α6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the α6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the α6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the α5 chain was undetectable. Our results show a restricted and differential distribution of the novel α6 and α5 chains in skeletal muscle when compared to the widely distributed, homologous α3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the α5 chain may have a specialized function in tissue areas subjected to tensile stress, the α6 chain appears implicated in ECM remodeling during muscle fibrosis.
胶原 VI 是细胞外基质（ECM）的主要蛋白之一，对维持骨骼肌的功能完整性具有重要作用。COL6A1、COL6A2 和 COL6A3 基因突变会导致 Ullrich 先天性肌肉营养不良症（UCMD）、Bethlem 肌病和肌硬化症。此外，Col6a1(-/-) 小鼠和胶原 VI 缺乏的斑马鱼表现出肌病表型。最近，在人类中又发现了两种额外的胶原 VI 链，即 α5 和 α6 链，但其在人类骨骼肌中的分布模式和功能尚未得到深入研究。通过免疫荧光分析，α6 链在肌内膜和肌周膜中被检测到，而 α5 链的标记仅限于肌-腱交界处。在正常的肌肉培养中，α6 链在 ECM 中仅以微量存在，而 α5 链则未被检测到。在缺乏抗坏血酸的情况下，α6 链主要积聚在一组肌间充质来源的、desmin 阴性细胞的细胞质中，这些细胞可被认为是肌成纤维细胞，因为它们表达α-平滑肌肌动蛋白。TGF-β1 是一种促纤维化因子，可诱导成纤维细胞向肌成纤维细胞转化，在添加抗坏血酸后，它增加了 α6 链在细胞外基质中的沉积。为了确定 α6 链在肌肉纤维化中的作用，我们研究了患有杜氏肌营养不良症（DMD）的患者的活检样本。我们发现，α6 链在纤维化区域显著上调，而在这些区域，α5 链则无法检测到。与广泛分布的同源 α3 链相比，我们的结果显示新的 α6 和 α5 链在骨骼肌中的分布具有受限性和差异性，这表明这些新链可能在特殊的 ECM 结构中发挥特定的作用。虽然 α5 链可能在受到张力的组织区域具有特殊功能，但 α6 链似乎参与了肌肉纤维化过程中的 ECM 重塑。
