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 ?5 and ?6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the ?6 chain was detected in the endomysium and perimysium, while the ?5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the ?6 chain was present in traces in the ECM, while the ?5 chain was not detected. In the absence of ascorbic acid, the ?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 ?-smooth muscle actin. TGF-?1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the ?6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the ?6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the ?6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the ?5 chain was undetectable. Our results show a restricted and differential distribution of the novel ?6 and ?5 chains in skeletal muscle when compared to the widely distributed, homologous ?3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the ?5 chain may have a specialized function in tissue areas subjected to tensile stress, the ?6 chain appears implicated in ECM remodeling during muscle fibrosis. Copyright 2012 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.
Expression of collagen VI alpha5 and alpha6 chains in human muscle and in Duchenne muscular dystrophy-related muscle fibrosis.
Sabatelli P;Squarzoni S;
2012
Abstract
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 ?5 and ?6 chains, however their distribution patterns and functions in human skeletal muscle have not been thoroughly investigated yet. By means of immunofluorescence analysis, the ?6 chain was detected in the endomysium and perimysium, while the ?5 chain labeling was restricted to the myotendinous junctions. In normal muscle cultures, the ?6 chain was present in traces in the ECM, while the ?5 chain was not detected. In the absence of ascorbic acid, the ?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 ?-smooth muscle actin. TGF-?1 treatment, a pro-fibrotic factor which induces trans-differentiation of fibroblasts into myofibroblasts, increased the ?6 chain deposition in the extracellular matrix after addition of ascorbic acid. In order to define the involvement of the ?6 chain in muscle fibrosis we studied biopsies of patients affected by Duchenne Muscular Dystrophy (DMD). We found that the ?6 chain was dramatically up-regulated in fibrotic areas where, in contrast, the ?5 chain was undetectable. Our results show a restricted and differential distribution of the novel ?6 and ?5 chains in skeletal muscle when compared to the widely distributed, homologous ?3 chain, suggesting that these new chains may play specific roles in specialized ECM structures. While the ?5 chain may have a specialized function in tissue areas subjected to tensile stress, the ?6 chain appears implicated in ECM remodeling during muscle fibrosis. Copyright 2012 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
