Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice

Elena Palma, Tania Tiepolo, Alessia Angelin, Patrizia Sabatelli, Nadir M. Maraldi, Emy Basso, Michael A. Forte, Paolo Bernardip, Paolo Bonaldo

Research output: Contribution to journalArticle

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2024-2031
Number of pages8
JournalHuman molecular genetics
Volume18
Issue number11
DOIs
StatePublished - May 19 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Palma, E., Tiepolo, T., Angelin, A., Sabatelli, P., Maraldi, N. M., Basso, E., Forte, M. A., Bernardip, P., & Bonaldo, P. (2009). Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice. Human molecular genetics, 18(11), 2024-2031. https://doi.org/10.1093/hmg/ddp126