Defective collagen VI alpha 6 chain expression in the skeletal muscle of patients with collagen VI-related myopathies

Collagen VI is a non-fibrillar collagen present in the extracellular matrix (ECM) as a complex polymer; the mainly expressed form is composed of alpha 1, alpha 2 and alpha 3 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 alpha 6 chain is a recently identified component of the ECM of the human skeletal muscle. Here we report that the alpha 6 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" alpha 1 alpha 2 alpha 3 heterotrimer. By contrast, the collagen VI alpha 6 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 TOE-beta 1, a potent collagen inducer, promoted the collagen VI a6 chain deposition in the ECM of normal muscle cells, whereas, in cultures derived from collagen VI-related myopathy patients, the collagen VI a6 chain failed to develop a network outside the cells and accumulated in the endoplasmic reticulum. The defect of the a6 chain points to a contribution to the pathogenesis of collagen VI-related disorders. (C) 2014 The Authors. Published by Elsevier B.V.