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The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1-/- myopathic mice
- Publication Year :
- 2009
- Publisher :
- WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA, 2009.
-
Abstract
- 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.
- Subjects :
- Ullrich congenital muscular dystrophy
Apoptosis
Collagen Type VI
Biology
Cyclophilins
Jurkat Cells
Mice
Muscular Diseases
Collagen VI
medicine
Animals
Humans
Mitochondria
Muscular dystrophy
Knockout mice
Muscle, Skeletal
Cyclophilin
Pharmacology
Mice, Knockout
cyclophilin
mitochondria
immunosuppression
Dose-Response Relationship, Drug
Bethlem myopathy
Skeletal muscle
medicine.disease
Molecular biology
Research Papers
Calcineurin
medicine.anatomical_structure
Biochemistry
Mitochondrial permeability transition pore
Cyclosporine
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....6a48991584c2e290ab4ff9dc50b46ab1