NIM811, a cyclophilin inhibitor without immunosuppressive activity, is beneficial in collagen VI congenital muscular dystrophy models.
Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are inherited muscle diseases due to mutations in the genes encoding the extracellular matrix protein collagen (Col) VI. Opening of the cyclosporin A-sensitive mitochondrial permeability transition pore (PTP) is a causative event in disease pathogenesis, and a potential target for therapy. Here, we have tested the effect of N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive cyclophilin inhibitor, in a zebrafish model of ColVI myopathy obtained by deletion of the N-terminal region of the ColVI α1 triple helical domain, a common mutation of UCMD. Treatment with antisense morpholino sequences targeting col6a1 exon 9 at the 1-4 cell stage (within 1 h post fertilization, hpf) caused severe ultrastructural and motor abnormalities as assessed by electron and fluorescence microscopy, birefringence, spontaneous coiling events and touch-evoked responses measured at 24-48 hpf. Structural and functional abnormalities were largely prevented when NIM811--which proved significantly more effective than cyclosporin A--was administered at 21 hpf, while FK506 was ineffective. Beneficial effects of NIM811 were also detected (i) in primary muscle-derived cell cultures from UCMD and BM patients, where the typical mitochondrial alterations and depolarizing response to rotenone and oligomycin were significantly reduced; and (ii) in the Col6a1(-/-) myopathic mouse model, where apoptosis was prevented and muscle strength was increased. Since the PTP of zebrafish shares its key regulatory features with the mammalian pore, our results suggest that early treatment with NIM811 should be tested as a potential therapy for UCMD and BM.
Department of Biomedical Sciences Consiglio Nazionale Delle Ricerche Neuroscience Institute, I-35131 Padova, Italy.
Alessandra
A
Zulian
Department of Biomedical Sciences Consiglio Nazionale Delle Ricerche Neuroscience Institute, I-35131 Padova, Italy.
Erika
E
Rizzo
Department of Biology and.
Marco
M
Schiavone
Department of Biomedical Sciences.
Elena
E
Palma
Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, I-40136 Bologna, Italy and.
Francesca
F
Tagliavini
Department of Biomedical Sciences.
Bert
B
Blaauw
Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, I-40136 Bologna, Italy and.
Luciano
L
Merlini
Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, I-40136 Bologna, Italy and.
Nadir Mario
NM
Maraldi
Laboratory of Musculoskeletal Cell Biology, Istituto Ortopedico Rizzoli, I-40136 Bologna, Italy and Consiglio Nazionale Delle Ricerche, Institute of Molecular Genetics, I-40136 Bologna, Italy.
Patrizia
P
Sabatelli
Department of Molecular Medicine, University of Padova, I-35131 Padova, Italy.
Paola
P
Braghetta
Department of Molecular Medicine, University of Padova, I-35131 Padova, Italy.
Paolo
P
Bonaldo
Department of Biology and.
Francesco
F
Argenton
Department of Biomedical Sciences Consiglio Nazionale Delle Ricerche Neuroscience Institute, I-35131 Padova, Italy, bernardi@bio.unipd.it.
Paolo
P
Bernardi
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism*; D016572:Cyclosporine / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D009136:Muscular Dystrophies / Q000151:congenital / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism*
C000598251:Col6a1 protein, zebrafish; D024142:Collagen Type VI; D029961:Zebrafish Proteins; D016572:Cyclosporine; C090438:(melle-4)cyclosporin