Human Molecular Genetics Advance Access published online on March 17, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp126
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Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice
1 Departments of Biomedical Sciences and University of Padova, 35121 Padova, Italy 2 Departments of Histology, Microbiology & Medical Biotechnologies, University of Padova, 35121 Padova, Italy. 3 IGM-CNR, Unit of Bologna c/o IOR, 40136 Bologna, Italy. 4 Vollum Institute, Oregon Health and Science University, Portland, OR 97239-3098, USA
Correspondence: Prof. Paolo Bonaldo, Dipartimento di Istologia, Microbiologia e Biotecnologie Mediche, Viale Giuseppe Colombo 3, I-35121 Padova, Italy, Phone +39 049 827 6084, Fax +39 049 827 6079, e-mail: bonaldo{at}bio.unipd.it; Prof. Paolo Bernardi, Dipartimento di Scienze Biomediche Sperimentali, Viale Giuseppe Colombo 3, I-35121 Padova, Italy, Phone +39 049 827 6365, Fax +39 049 827 6361, e-mail: bernardi{at}bio.unipd.it
Received January 23, 2009; Revised March 12, 2009; Accepted March 13, 2009
Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy are inherited muscle disorders caused by mutations of genes encoding the extracellular matrix protein collagen VI. Mice lacking collagen VI (Col6a1–/–) display a myopathic phenotype associated with ultrastructural alterations of mitochondria and sarcoplasmic reticulum, mitochondrial dysfunction with abnormal opening of the permeability transition pore (PTP), and increased apoptosis of muscle fibers. Treatment with cyclosporin (Cs) A, a drug that desensitizes the PTP by binding to cyclophilin (Cyp) D, was shown to rescue myofiber alterations in Col6a1–/– mice and in UCMD patients, suggesting a correlation between PTP opening and pathogenesis of collagen VI muscular dystrophies. Here we show that inactivation of the gene encoding for Cyp-D rescues the disease phenotype of collagen VI deficiency. In the absence of Cyp-D, Col6a1–/– mice show negligible myofiber degeneration, rescue from mitochondrial dysfunction and ultrastructural defects, and normalized incidence of apoptosis. These findings (i) demonstrate that lack of Cyp-D is equivalent to its inhibition with CsA at curing the mouse dystrophic phenotype; (ii) establish a cause-effect relationship between Cyp-D-dependent PTP regulation and pathogenesis of the collagen VI muscular dystrophy; and (iii) validate Cyp-D and the PTP as pharmacological targets for the therapy of human collagen VI myopathies.
* These authors contributed equally.
Abbreviations: ColVI, collagen VI; Cs, cyclosporin; CyP, cyclophilin; DMEM, Dulbecco's modified Eagle medium; EBD, Evans blue dye; FCS, fetal calf serum; FDB, flexor digitorum brevis; PTP, permeability transition pore; TMRM, tetramethylrhodamine methyl ester; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling; UCMD, Ullrich congenital muscular dystrophy.
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