Collagen VI is an extra-cellular matrix protein that forms a micro-filamentous network in skeletal muscles and other organs. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem Myopathy and Ullrich congenital muscular dystrophy. We previously generated collagen VI-deficient (Col VI KO) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy. The patho-physiological defects and mechanisms leading to the mypathic disorder were not known. Our results reveal that  the Col VI KO muscles have a loss of contractile strength associated with ultra-structural alterations of the sarcoplasmic reticulum (SR) and mitochondria with spontaneous apoptosis. A latent mitochondrial dysfunction was demonstrated in Col VI KO myofibers on incubation with the mitochondrial F1F0 ATP synthase inhibitor oligomycin, which caused mitochondrial depolarization, calcium de-regulation and increased apoptosis. These pathological defects were reversible, as they could be normalized by plating the Col VI KO myofibers on collagen VI or by the addition of cyclosporin A (CsA), the potent inhibitor of the mitochondrial permeability transition (PTP, a mediator of apoptosis). Treatment of the collagen VI KO mice with CsA rescued the muscle ultra-structural defects and markedly decreased the number of apoptotic nuclei in vivo. These findings indicate that collagen VI myopathies have an unexpected mitochondrial pathogenesis that could be exploited for therapeutic intervention.

Predsjednica HGD-a:
Dr. sc. Ðurðica Ugarkoviæ, zn. savjetnica, IRB

Koordinatori predavanja:
Dr. sc. Ksenija Zahradka, zn. sur., IRB
Dr. sc. Krešimir Gjuraèiæ, Pliva Istraživaèki Institut d.o.o.