title: Mitochondrial DNA deletions in muscle satellite cells: implications for therapies.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, The Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
authors.forename: Sally
authors.initials: S
authors.lastname: Spendiff
authors.forename: Mojgan
authors.initials: M
authors.lastname: Reza
authors.forename: Julie L
authors.initials: JL
authors.lastname: Murphy
authors.forename: Grainne
authors.initials: G
authors.lastname: Gorman
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Georgia
authors.initials: G
authors.lastname: Campbell
authors.forename: Jane
authors.initials: J
authors.lastname: Newman
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Doug M
authors.initials: DM
authors.lastname: Turnbull
mesh_terms: D000328:Adult; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D017240:Mitochondrial Myopathies / Q000235:genetics* / Q000628:therapy; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics; D012337:RNA, Ribosomal, 18S / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D032496:Satellite Cells, Skeletal Muscle / Q000378:metabolism*
chemical_list: D004272:DNA, Mitochondrial; D009245:NADH Dehydrogenase; D012337:RNA, Ribosomal, 18S; C515075:NADH dehydrogenase subunit 1, human