The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice
Article first published online: 10 JUN 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Volume 157, Issue 6, pages 1045–1052, July 2009
How to Cite
Tiepolo, T., Angelin, A., Palma, E., Sabatelli, P., Merlini, L., Nicolosi, L., Finetti, F., Braghetta, P., Vuagniaux, G., Dumont, J.-M., Baldari, C., Bonaldo, P. and Bernardi, P. (2009), The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1−/− myopathic mice. British Journal of Pharmacology, 157: 1045–1052. doi: 10.1111/j.1476-5381.2009.00316.x
- Issue published online: 13 JUL 2009
- Article first published online: 10 JUN 2009
- Received 18 March 2009; accepted 19 March 2009
- permeability transition;
- cell death;
- collagen VI;
- muscular dystrophies
Background and purpose: We have investigated the therapeutic effects of the selective cyclophilin inhibitor D-MeAla3-EtVal4-cyclosporin (Debio 025) in myopathic Col6a1−/− mice, a model of muscular dystrophies due to defects of collagen VI.
Experimental approach: We studied calcineurin activity based on NFAT translocation; T cell activation based on expression of CD69 and CD25; propensity to open the permeability transition pore in mitochondria and skeletal muscle fibres based on the ability to retain Ca2+ and on membrane potential, respectively; muscle ultrastructure by electronmicroscopy; and apoptotic rates by terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling assays in Col6a1−/− mice before after treatment with Debio 025.
Key results: Debio 025 did not inhibit calcineurin activity, yet it desensitizes the mitochondrial permeability transition pore in vivo. Treatment with Debio 025 prevented the mitochondrial dysfunction and normalized the apoptotic rates and ultrastructural lesions of myopathic Col6a1−/− mice.
Conclusions and implications: Desensitization of the mitochondrial permeability transition pore can be achieved by selective inhibition of matrix cyclophilin D without inhibition of calcineurin, resulting in an effective therapy of Col6a1−/− myopathic mice. These findings provide an important proof of principle that collagen VI muscular dystrophies can be treated with Debio 025. They represent an essential step towards an effective therapy for Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy, because Debio 025 does not expose patients to the potentially harmful effects of immunosuppression.