Journal Article

Mitochondrial DNA deletions in muscle satellite cells: implications for therapies

Sally Spendiff, Mojgan Reza, Julie L. Murphy, Grainne Gorman, Emma L. Blakely, Robert W. Taylor, Rita Horvath, Georgia Campbell, Jane Newman, Hanns Lochmüller and Doug M. Turnbull

in Human Molecular Genetics

Volume 22, issue 23, pages 4739-4747
Published in print December 2013 | ISSN: 0964-6906
Published online July 2013 | e-ISSN: 1460-2083 | DOI:

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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.

Journal Article.  6072 words.  Illustrated.

Subjects: Genetics and Genomics

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