Collagen VI is an extracellular matrix protein that forms a microfilamentous network in skeletal muscles and other organs^1,2,3. Inherited mutations in genes encoding collagen VI in humans cause two muscle diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy^4,5. We previously generated collagen VI–deficient (Col6a1^−/−) mice and showed that they have a muscle phenotype that strongly resembles Bethlem myopathy⁶. The pathophysiological defects and mechanisms leading to the myopathic disorder were not known. Here we show that Col6a1^−/− muscles have a loss of contractile strength associated with ultrastructural alterations of sarcoplasmic reticulum (SR) and mitochondria and spontaneous apoptosis. We found a latent mitochondrial dysfunction in myofibers of Col6a1^−/− mice on incubation with the selective F₁F_O-ATPase inhibitor oligomycin, which caused mitochondrial depolarization, Ca²⁺ deregulation and increased apoptosis. These defects were reversible, as they could be normalized by plating Col6a1^−/− myofibers on collagen VI or by addition of cyclosporin A (CsA), the inhibitor of mitochondrial permeability transition pore (PTP). Treatment of Col6a1^−/− mice with CsA rescued the muscle ultrastructural 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.

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