title: Critical evaluation of the use of cell cultures for inclusion in clinical trials of patients affected by collagen VI myopathies.
abstract: Collagen VI myopathies (Ullrich congenital muscular dystrophy (UCMD), Bethlem myopathy (BM), and myosclerosis myopathy) share a common pathogenesis, that is, mitochondrial dysfunction due to deregulation of the permeability transition pore (PTP). This effect was first identified in the Col6a1(-/-) mouse model and then in muscle cell cultures from UCMD and BM patients; the normalizing effect of cyclosporin A (CsA) confirmed the pathogenic role of PTP opening. In order to determine whether mitochondrial performance can be used as a criterion for inclusion in clinical trials and as an outcome measure of the patient response to therapy, it is mandatory to establish whether mitochondrial dysfunction is conserved in primary cell cultures from UCMD and BM patients. In this study we report evidence that mitochondrial dysfunction and the consequent increase of apoptotic rate can be detected not only, as previously reported, in muscle, but also in fibroblast cell cultures established from muscle biopsies of collagen VI-related myopathic patients. However, the mitochondrial phenotype is no longer maintained after nine passages in culture. These data demonstrate that the dire consequences of mitochondrial dysfunction are not limited to myogenic cells, and that this parameter can be used as a suitable diagnostic criterion, provided that the cell culture conditions are carefully established.
authors.affiliation: CNR-National Research Council of Italy, Institute of Molecular Genetics c/o IOR, Bologna, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Sabatelli
authors.forename: E
authors.initials: E
authors.lastname: Palma
authors.forename: A
authors.initials: A
authors.lastname: Angelin
authors.forename: S
authors.initials: S
authors.lastname: Squarzoni
authors.forename: A
authors.initials: A
authors.lastname: Urciuolo
authors.forename: C
authors.initials: C
authors.lastname: Pellegrini
authors.forename: T
authors.initials: T
authors.lastname: Tiepolo
authors.forename: P
authors.initials: P
authors.lastname: Bonaldo
authors.forename: F
authors.initials: F
authors.lastname: Gualandi
authors.forename: L
authors.initials: L
authors.lastname: Merlini
authors.forename: P
authors.initials: P
authors.lastname: Bernardi
authors.forename: N M
authors.initials: NM
authors.lastname: Maraldi
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D002986:Clinical Trials as Topic / Q000379:methods*; D024142:Collagen Type VI / Q000378:metabolism*; D003286:Contracture / Q000378:metabolism / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009135:Muscular Diseases / Q000378:metabolism* / Q000473:pathology*; D009136:Muscular Dystrophies / Q000151:congenital / Q000378:metabolism / Q000473:pathology; D017063:Outcome Assessment, Health Care; D018579:Patient Selection; D010641:Phenotype; D061251:Primary Cell Culture; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology
chemical_list: D024142:Collagen Type VI