Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers.
Skeletal muscle-mass loss with age has severe health consequences, yet the molecular basis of the loss remains obscure. Although mitochondrial DNA (mtDNA)-deletion mutations have been shown to accumulate with age, for these aberrant genomes to be physiologically relevant, they must accumulate to high levels intracellularly and be present in a significant number of cells. We examined mtDNA-deletion mutations in vastus lateralis (VL) muscle of human subjects aged 49-93 years, using both histologic and polymerase-chain-reaction (PCR) analyses, to determine the physiological and genomic integrity of mitochondria in aging human muscle. The number of VL muscle fibers exhibiting mitochondrial electron-transport-system (ETS) abnormalities increased from an estimated 6% at age 49 years to 31% at age 92 years. We analyzed the mitochondrial genotype of 48 single ETS-abnormal, cytochrome c oxidase-negative/succinate dehydrogenase-hyperreactive (COX-/SDH++) fibers from normal aging human subjects and identified mtDNA-deletion mutations in all abnormal fibers. Deletion mutations were clonal within a fiber and concomitant to the COX-/SDH++ region. Quantitative PCR analysis of wild-type and deletion-containing mtDNA genomes within ETS-abnormal regions of single fibers demonstrated that these deletion mutations accumulate to detrimental levels (>90% of the total mtDNA).
Bua
Entela
E
Department of Animal Health and Biomedical Sciences, University of Wisconsin, Madison, WI 53706, USA.
Johnson
Jody
J
Herbst
Allen
A
Delong
Bridget
B
McKenzie
Debbie
D
Salamat
Shahriar
S
Aiken
Judd M
JM
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics*; D004579:Electron Transport / Q000235:genetics; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000737:chemistry / Q000166:cytology / Q000201:enzymology*; D017384:Sequence Deletion; D013385:Succinate Dehydrogenase / Q000235:genetics
D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; D013385:Succinate Dehydrogenase; D003576:Electron Transport Complex IV