Document Detail

Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
MedLine Citation:
PMID:  19293339     Owner:  NLM     Status:  MEDLINE    
Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy are inherited muscle disorders caused by mutations of genes encoding the extracellular matrix protein collagen VI (ColVI). Mice lacking ColVI (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 ColVI muscular dystrophies. Here, we show that inactivation of the gene encoding for Cyp-D rescues the disease phenotype of ColVI 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 ColVI muscular dystrophy and (iii) validate Cyp-D and the PTP as pharmacological targets for the therapy of human ColVI myopathies.
Elena Palma; Tania Tiepolo; Alessia Angelin; Patrizia Sabatelli; Nadir M Maraldi; Emy Basso; Michael A Forte; Paolo Bernardi; Paolo Bonaldo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-03-17
Journal Detail:
Title:  Human molecular genetics     Volume:  18     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2009 Jun 
Date Detail:
Created Date:  2009-05-08     Completed Date:  2009-07-30     Revised Date:  2011-11-24    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  2024-31     Citation Subset:  IM    
Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
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MeSH Terms
Cells, Cultured
Collagen Type VI / genetics*,  metabolism
Cyclophilins / genetics*,  metabolism
Disease Models, Animal
Gene Silencing*
Mice, Inbred C57BL
Mice, Knockout
Mitochondria / enzymology*,  genetics,  metabolism
Muscle Fibers, Skeletal / cytology*,  enzymology,  metabolism
Muscular Diseases / enzymology,  genetics,  metabolism,  physiopathology*
Grant Support
Reg. No./Substance:
0/Col6a1 protein, mouse; 0/Collagen Type VI; EC 5.2.1.-/Cyclophilins; EC D

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