title: Genetic ablation of cyclophilin D rescues mitochondrial defects and prevents muscle apoptosis in collagen VI myopathic mice.
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.
authors.affiliation: Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Palma
authors.forename: Tania
authors.initials: T
authors.lastname: Tiepolo
authors.forename: Alessia
authors.initials: A
authors.lastname: Angelin
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Emy
authors.initials: E
authors.lastname: Basso
authors.forename: Michael A
authors.initials: MA
authors.lastname: Forte
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonaldo
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D024142:Collagen Type VI / Q000235:genetics* / Q000378:metabolism; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D009135:Muscular Diseases / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C540085:Col6a1 protein, mouse; D024142:Collagen Type VI; D000081406:Peptidyl-Prolyl Isomerase F; C000631446:PPIF protein, mouse; D021983:Cyclophilins