Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers

Am J Hum Genet. 2006 Sep;79(3):469-80. doi: 10.1086/507132. Epub 2006 Jul 7.


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).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Aged, 80 and over
  • Aging / genetics*
  • DNA, Mitochondrial / analysis
  • DNA, Mitochondrial / genetics*
  • Electron Transport / genetics
  • Electron Transport Chain Complex Proteins / genetics*
  • Electron Transport Complex IV / genetics
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mitochondria, Muscle / enzymology
  • Mitochondria, Muscle / genetics
  • Muscle Fibers, Skeletal / chemistry
  • Muscle Fibers, Skeletal / cytology
  • Muscle Fibers, Skeletal / enzymology*
  • Muscle, Skeletal / chemistry
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / enzymology*
  • Sequence Deletion
  • Succinate Dehydrogenase / genetics


  • DNA, Mitochondrial
  • Electron Transport Chain Complex Proteins
  • Succinate Dehydrogenase
  • Electron Transport Complex IV