title: The cyclophilin inhibitor Debio 025 normalizes mitochondrial function, muscle apoptosis and ultrastructural defects in Col6a1-/- myopathic mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Histology, University of Padova, I-35121 Padova, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Tiepolo
authors.forename: A
authors.initials: A
authors.lastname: Angelin
authors.forename: E
authors.initials: E
authors.lastname: Palma
authors.forename: P
authors.initials: P
authors.lastname: Sabatelli
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: L
authors.initials: L
authors.lastname: Nicolosi
authors.forename: F
authors.initials: F
authors.lastname: Finetti
authors.forename: P
authors.initials: P
authors.lastname: Braghetta
authors.forename: G
authors.initials: G
authors.lastname: Vuagniaux
authors.forename: J-M
authors.initials: JM
authors.lastname: Dumont
authors.forename: C T
authors.initials: CT
authors.lastname: Baldari
authors.forename: P
authors.initials: P
authors.lastname: Bonaldo
authors.forename: P
authors.initials: P
authors.lastname: Bernardi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D024142:Collagen Type VI / Q000172:deficiency* / Q000235:genetics; D021983:Cyclophilins / Q000037:antagonists & inhibitors* / Q000502:physiology; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure*; D009135:Muscular Diseases / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*
chemical_list: C540085:Col6a1 protein, mouse; D024142:Collagen Type VI; D016572:Cyclosporine; D021983:Cyclophilins; C499715:alisporivir