Mitochondrial DNA deletions in muscle satellite cells: implications for therapies

Progressive myopathy is a major clinical feature of patients with mitochondrial DNA (mtDNA) disease. There is limited treatment available for these patients although exercise and other approaches to activate muscle stem cells (satellite cells) have been proposed. The majority of mtDNA defects are he...

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Bibliographic Details
Published in:Human molecular genetics 2013-12, Vol.22 (23), p.4739-4747
Main Authors: Spendiff, Sally, Reza, Mojgan, Murphy, Julie L, Gorman, Grainne, Blakely, Emma L, Taylor, Robert W, Horvath, Rita, Campbell, Georgia, Newman, Jane, Lochmüller, Hanns, Turnbull, Doug M
Format: Article
Language:English
Subjects:
Adult
DNA Copy Number Variations
DNA, Mitochondrial - genetics
Female
Gene Deletion
Genetic Variation
Genotype
Humans
Male
Middle Aged
Mitochondria - drug effects
Mitochondria - genetics
Mitochondria - pathology
Mitochondrial Myopathies - genetics
Mitochondrial Myopathies - therapy
Muscle Fibers, Skeletal - metabolism
Mutation
NADH Dehydrogenase - genetics
Real-Time Polymerase Chain Reaction
RNA, Ribosomal, 18S - genetics
Satellite Cells, Skeletal Muscle - metabolism
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Summary:Progressive myopathy is a major clinical feature of patients with mitochondrial DNA (mtDNA) disease. There is limited treatment available for these patients although exercise and other approaches to activate muscle stem cells (satellite cells) have been proposed. The majority of mtDNA defects are heteroplasmic (a mixture of mutated and wild-type mtDNA present within the muscle) with high levels of mutated mtDNA and low levels of wild-type mtDNA associated with more severe disease. The culture of satellite cell-derived myoblasts often reveals no evidence of the original mtDNA mutation although it is not known if this is lost by selection or simply not present in these cells. We have explored if the mtDNA mutation is present in the satellite cells in one of the commonest genotypes associated with mitochondrial myopathies (patients with single, large-scale mtDNA deletions). Analysis of satellite cells from eight patients showed that the level of mtDNA mutation in the satellite cells is the same as in the mature muscle but is most often subsequently lost during culture. We show that there are two periods of selection against the mutated form, one early on possibly during satellite cell activation and the other during the rapid replication phase of myoblast culture. Our data suggest that the mutations are also lost during rapid replication in vivo, implying that strategies to activate satellite cells remain a viable treatment for mitochondrial myopathies in specific patient groups.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddt327