title: Accumulation of mitochondrial DNA deletion mutations in aged muscle fibers: evidence for a causal role in muscle fiber loss.
abstract: Although mitochondrial mutation abundance has been recognized to increase in an age-dependent manner, the impact of mutation has been more difficult to establish. Using quantitative polymerase chain reaction, we measured the intracellular abundance of mutant and wild-type mitochondrial genomes along the length of individual laser-captured microdissected muscle fibers from aged rat quadriceps. Aged muscle fibers possessed segmental, clonal intracellular expansions of unique somatically derived mitochondrial DNA (mtDNA) deletion mutations. When the mutation abundance surpassed 90% of the total mitochondrial genomes, the fiber lost cytochrome c oxidase activity and exhibited an increase in succinate dehydrogenase activity. In addition to the mitochondrial enzymatic abnormalities, some fibers displayed abnormal morphology such as fiber splitting, atrophy, and breakage. Deletion mutation accumulation was linked to these aberrant morphologies with more severe cellular pathologies resulting from higher deletion mutation abundance. In summary, our measurements indicate that age-induced mtDNA deletion mutations expand within individual muscle fibers, eliciting fiber dysfunction and breakage.
authors: University of Wisconsin, Department of Animal Health and Biomedical Sciences, Madison, WI 53706, USA.
authors: Allen
authors: A
authors: Herbst
authors: Jeong W
authors: JW
authors: Pak
authors: Debbie
authors: D
authors: McKenzie
authors: Entela
authors: E
authors: Bua
authors: Marwa
authors: M
authors: Bassiouni
authors: Judd M
authors: JM
authors: Aiken
mesh_terms: D000375:Aging / Q000235:genetics*; D000818:Animals; D001284:Atrophy; D002999:Clone Cells; D053960:DNA Breaks; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D016678:Genome / Q000235:genetics; D053685:Laser Therapy; D008297:Male; D042282:Microdissection; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D017384:Sequence Deletion / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV