Cultured muscle cells display defects of mitochondrial myopathy ameliorated by a

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Brain. 2007 Jul 11

Cultured muscle cells display defects of mitochondrial myopathy

ameliorated by anti-oxidants.

Vergani L, Malena A, Sabatelli P, Loro E, Cavallini L, Magalhaes P,

Valente L, Bragantini F, Carrara F, Langer B, Poulton J, AP,

Holt IJ.

Department of Neurological Sciences, University of Padova, 35129

Padova, ITOI-CNR IOP, 40136 Bologna, Departments of Biochemistry and

Biomedical Sciences, University of Padova, 35121 Padova, Department

of Molecular Neurogenetics, National Neurological Institute C.Besta,

20126 Milano, Italy, Clinique Romande de Readaptation, CH-1951 Sion,

Switzerland, Department of Obstetrics and Gynaecology, J Radcliffe

Hospital, OX3 9DU Oxford, UK, School of Exercise and Nutrition

Sciences, Deakin University, 3125 Australia and MRC-Dunn Human

Nutrition Unit, University of Cambridge, CB2 OXY Cambridge, UK.

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.