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Brain Advance Access originally published online on July 11, 2007
Brain 2007 130(10):2715-2724; doi:10.1093/brain/awm151
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cultured muscle cells display defects of mitochondrial myopathy ameliorated by anti-oxidants

Lodovica Vergani1, Adriana Malena1, Patrizia Sabatelli2, Emanuele Loro1, Lucia Cavallini3, Paolo Magalhaes4, Lucia Valente1,5, Federica Bragantini1, Franco Carrara5, Bertrand Leger6, Joanna Poulton7, Aaron P. Russell6,8 and Ian J. Holt9

1Department of Neurological Sciences, University of Padova, 35129 Padova, 2ITOI-CNR IOP, 40136 Bologna, Departments of 3Biochemistry and 4Biomedical Sciences, University of Padova, 35121 Padova, 5Department of Molecular Neurogenetics, National Neurological Institute C.Besta, 20126 Milano, Italy, 6Clinique Romande de Readaptation, CH-1951 Sion, Switzerland, 7Department of Obstetrics and Gynaecology, J Radcliffe Hospital, OX3 9DU Oxford, UK, 8School of Exercise and Nutrition Sciences, Deakin University, 3125 Australia and 9MRC-Dunn Human Nutrition Unit, University of Cambridge, CB2 OXY Cambridge, UK

Correspondence to: L. Vergani, c/o Venetian Institute of Molecular Medicine, via Orus, 2; 35129 Padova, Italy E-mail: lodovica.vergani{at}unipd.it

The mitochondrial DNA A3243G mutation causes neuromuscular disease. To investigate the muscle-specific pathophysiology of mitochondrial disease, rhabdomyosarcoma transmitochondrial hybrid cells (cybrids) were generated that retain the capacity to differentiate to myotubes. In some cases, striated muscle-like fibres were formed after innervation with rat embryonic spinal cord. Myotubes carrying A3243G mtDNA produced more reactive oxygen species than controls, and had altered glutathione homeostasis. Moreover, A3243G mutant myotubes showed evidence of abnormal mitochondrial distribution, which was associated with down-regulation of three genes involved in mitochondrial morphology, Mfn1, Mfn2 and DRP1. Electron microscopy revealed mitochondria with ultrastructural abnormalities and paracrystalline inclusions. All these features were ameliorated by anti-oxidant treatment, with the exception of the paracrystalline inclusions. These data suggest that rhabdomyosarcoma cybrids are a valid cellular model for studying muscle-specific features of mitochondrial disease and that excess reactive oxygen species production is a significant contributor to mitochondrial dysfunction, which is amenable to anti-oxidant therapy.

Key Words: Cybrids; MELAS; Differentiation; ROS

Abbreviations: cybrids, transmitochondrial hybrid cell; LHON, Leber's Hereditary Optic Neuropathy; MS, clones of cybrids harbouring mutant mtDNA; NARP, Neuropathy, Ataxia and Retinitis Pigmentosa; Opa 1, Optic Atrophy 1; OXPHOS, oxidative phosphorilation; PBS, phosphate saline buffer; qPCR, quantitative polymerase chain reaction; RD {rho}0, rhabdomyosarcoma cells without mitochondrial DNA; WT, clones of cybrids with normal (wild type) mitochondrial DNA

Received March 2, 2007. Revised May 10, 2007. Accepted June 6, 2007.


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