The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects
T Tiepolo1, A Angelin, E Palma
1Department of Histology, University of Padova, I-35121 Padova, Italy.
Background And Purpose:
We have investigated the therapeutic effects of the selective cyclophilin inhibitor D-MeAla(3)-EtVal(4)-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 Ca(2+) 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.
Insights
The drug Debio 025 effectively treats collagen VI muscular dystrophy in mice by desensitizing the mitochondrial permeability transition pore without causing immunosuppression.
Area of Science:
- Mitochondrial Biology
- Musculoskeletal Disorders
- Pharmacology
Background:
- Muscular dystrophies are often caused by defects in collagen VI.
- Col6a1(-/-) mice serve as a model for studying these conditions.
Purpose of the Study:
- To investigate the therapeutic effects of Debio 025, a selective cyclophilin inhibitor, in a mouse model of collagen VI-related muscular dystrophy.
- To determine if Debio 025 can ameliorate disease pathology without causing immunosuppression.
Main Methods:
- Assessed calcineurin activity via NFAT translocation.
- Measured T cell activation markers (CD69, CD25).
- Evaluated mitochondrial permeability transition pore propensity and Ca(2+) retention.
- Analyzed muscle ultrastructure using electron microscopy.
- Quantified apoptotic rates using TUNL assays in Col6a1(-/-) mice before and after Debio 025 treatment.
Main Results:
- Debio 025 desensitized the mitochondrial permeability transition pore in vivo.
- Treatment prevented mitochondrial dysfunction and normalized apoptosis and ultrastructural damage in Col6a1(-/-) mice.
- Debio 025 did not inhibit calcineurin activity.
Conclusions:
- Selective inhibition of matrix cyclophilin D desensitizes the mitochondrial permeability transition pore, offering an effective therapy for Col6a1(-/-) myopathic mice.
- This provides a proof of principle for treating collagen VI muscular dystrophies with Debio 025.
- Debio 025 represents a promising therapeutic strategy for Ullrich Congenital Muscular Dystrophy and Bethlem Myopathy, avoiding immunosuppressive side effects.
