Expression of collagen VI 伪5 and 伪6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis

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• 作者：Patrizia Sabatelli^a ; ^{sabatelli@area.bo.cnr.it} ; Francesca Gualandi^b ; Sudheer Kumar Gara^c ; Paolo Grumati^d ; Alessandra Zamparelli^e ; Elena Martoni^b ; Camilla Pellegrini^b ; Luciano Merlini^e ; Alessandra Ferlini^b ; Paolo Bonaldo^d ; Nadir Mario Maraldi^e ; Mats Paulsson^c ; ^f ; ^g ; Stefano Squarzoni^a ; ¹ ; ^{squarzoni@area.bo.cnr.it} ; Raimund Wagener^c ; ^f ; ¹
• 关键词：Collagen VI ; Skeletal muscle ; Myotendinous junctions ; Fibrosis ; Duchenne muscular dystrophy
• 刊名：Matrix Biology
• 出版年：2012
• 期刊代码：64_0945053x
• 类别：imm
• 出版时间：April, 2012
• 卷：31
• 期：3
• 页码：187-196
• 文件大小：1274 K

摘要

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^鈭?鈭?/em> mice and collagen VI deficient zebrafish display a myopathic phenotype. Recently, two additional collagen VI chains were identified in humans, the 伪5 and 伪6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the 伪6 chain was detected in the endomysium and perimysium, while the 伪5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the 伪6 chain was present in traces in the ECM, while the 伪5 chain was not detected. In the absence of ascorbic acid, the 伪6 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 伪-smooth muscle actin. TGF-尾1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the 伪6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the 伪6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the 伪6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the 伪5 chain was undetectable. Our results show a restricted and differential distribution of the novel 伪6 and 伪5 chains in skeletal muscle when compared to the widely distributed, homologous 伪3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the 伪5 chain may have a specialized function in tissue areas subjected to tensile stress, the 伪6 chain appears implicated in ECM remodeling during muscle fibrosis.