Collagen VI myopathies: from the animal model to the clinical trial.

Previous studies of our group provided newinsights in the pathogenic mechanisms of some types of muscular dystrophies, including those caused by mutations in genes encoding nuclear envelope proteins (Maraldi et al., 2003, 2006, 2007). Here we report recent progress in the identification of the pathogenic mechanism of muscular dystrophies due to mutations in the genes which encode any of the three chains of collagen VI, referred to as Bethlem myopathy (BM) and Ullrich congenital muscular dystrophy (UCMD. Extracellular matrix (ECM) and basal lamina molecular components are crucial for muscle cell adhesion, stability, and regeneration. Muscle cells are individually surrounded by a basal lamina which interacts with ECM constituents that contribute to their stability during contraction. A major component of the muscular ECM is collagen VI, which forms a microfibrillar network in association with the basal lamina. The data we obtained, initially in Col6a1 deficient mice, and subsequently on muscle biopsies of UCMD patients, indicate that the pathogenic mechanism, based on an unexpected collagen/mitochondrial connection, resides in an abnormal latent mitochondrial depolarization that results in the release of apoptotic factors that cause muscle degeneration. Furthermore, we discuss the possibility of reverting the altered mitochondrial phenotype by a pharmacological treatment of both Col6a1 deficient mice and muscle cells obtained from UCMD patients with cyclosporine A, based on its noncovalent binding to cyclophilin D, a matrix regulatory component of the permeability transition pore of the mitochondrial inner membrane. Finally, we report the promising results of an open pilot trial of UCMD and BM patients, which demonstrate that the treatment with cyclosporine A does not only desensitize the permeability transition pore, but significantly reduces muscle fibre apoptosis and increases muscle regeneration