Human Molecular Genetics, Vol 6, 2239-2242, Copyright © 1997 by Oxford University Press
EA Shoubridge, T Johns and G Karpati
Replicative segregation of mitochondrial DNA (mtDNA) can produce large
differences in the proportions of wild-type and mutant mtDNAs in different
cell types of patients with mitochondrial encephalomyopathy. This is
particularly striking in the skeletal muscle of patients with Kearns-Sayre
syndrome (KSS), a sporadic disease associated with large- scale mtDNA
deletions, and in sporadic patients with tRNA point mutations. Although the
skeletal muscle fibres of these patients invariably contain a large
proportion of mutant mtDNAs, mutant mtDNAs are rare or undetectable in
satellite cells cultured from the same muscle biopsy specimens. Since
satellite cells are responsible for muscle fibre regeneration, restoration
of the wild-type mtDNA genotype might be achieved in these patients by
encouraging muscle regeneration. To test this concept, we re-biopsied a
patient with a KSS phenotype and a mtDNA point mutation in the
tRNAleu(CUN)gene and analysed muscle fibres regenerating at the site of the
original muscle biopsy. Regenerating fibres were identified by
morphological criteria and by expression of neural cell adhesion molecule
(NCAM). All such fibers were positive for cytochrome c oxidase (COX)
activity by cytochemistry and essentially homoplasmic for wild-type mtDNA,
while the majority of non-regenerating fibres were COX-negative and
contained predominantly mutant mtDNAs. These results demonstrate that it
may be possible to improve muscle function in similar patients by methods
that promote satellite cell incorporation into existing myofibres.
ARTICLES
Complete restoration of a wild-type mtDNA genotype in regenerating muscle fibres in a patient with a tRNA point mutation and mitochondrial encephalomyopathy
Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. eric@ericpc.mni.mcgill.ca
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