Defective collagen VI α6 chain expression in the skeletal muscle of patients with collagen VI-related myopathies

• Published in: Biochimica et biophysica acta 2014-09, Vol.1842 (9), p.1604-1612
• Main Authors: Tagliavini, F., Pellegrini, C., Sardone, F., Squarzoni, S., Paulsson, M., Wagener, R., Gualandi, F., Trabanelli, C., Ferlini, A., Merlini, L., Santi, S., Maraldi, N.M., Faldini, C., Sabatelli, P.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Blotting, Western; Cells, Cultured; Child; Child, Preschool; Collagen Type VI - genetics; Collagen Type VI - metabolism; Collagen VI myopathies; Collagen VI α6 chain; Contracture - genetics; Contracture - metabolism; Contracture - pathology; Extracellular matrix; Extracellular Matrix - metabolism; Fibrosis; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Middle Aged; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Dystrophies - congenital; Muscular Dystrophies - genetics; Muscular Dystrophies - metabolism; Muscular Dystrophies - pathology; Mutation - genetics; Phenotype; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Sclerosis - genetics; Sclerosis - metabolism; Sclerosis - pathology; TGF-β1; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Young Adult
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2014.05.033

Collagen VI is a non-fibrillar collagen present in the extracellular matrix (ECM) as a complex polymer; the mainly expressed form is composed of α1, α2 and α3 chains; mutations in genes encoding these chains cause myopathies known as Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM) and myosclerosis myopathy (MM). The collagen VI α6 chain is a recently identified component of the ECM of the human skeletal muscle. Here we report that the α6 chain was dramatically reduced in skeletal muscle and muscle cell cultures of genetically characterized UCMD, BM and MM patients, independently of the clinical phenotype, the gene involved and the effect of the mutation on the expression of the “classical” α1α2α3 heterotrimer. By contrast, the collagen VI α6 chain was normally expressed or increased in the muscle of patients affected by other forms of muscular dystrophy, the overexpression matching with areas of increased fibrosis. In vitro treatment with TGF-β1, a potent collagen inducer, promoted the collagen VI α6 chain deposition in the ECM of normal muscle cells, whereas, in cultures derived from collagen VI-related myopathy patients, the collagen VI α6 chain failed to develop a network outside the cells and accumulated in the endoplasmic reticulum. The defect of the α6 chain points to a contribution to the pathogenesis of collagen VI-related disorders. •Collagen VI is an ECM component of the human skeletal muscle.•We evaluated the α6 chain in collagen VI-related and other muscular dystrophies.•The α6 chain was reduced in collagen VI-related diseases but not in other myopathies.•A correlation between the α6 chain and fibrosis was demonstrated in MDC1A.•The α6 chain is involved in the pathogenesis of collagen VI diseases and fibrosis.