Skeletal muscle mitochondrial DNA injury in patients with unilateral peripheral arterial disease

Circulation. 1999 Feb 16;99(6):807-12. doi: 10.1161/01.cir.99.6.807.


Background: Patients with peripheral arterial disease (PAD) have exercise limitation due to claudication-limited pain and metabolic alterations in skeletal muscle. PAD is also associated with oxidative stress, which is a known cause of mitochondrial DNA (mtDNA) injury. The present study was designed to test the hypothesis that PAD is associated with mtDNA injury, as reflected by an increased frequency of a specific 4977-base pair (bp) mtDNA deletion mutation.

Methods and results: The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subjects with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increased deletion frequency and the hemodynamically affected (worse affected) PAD limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse-affected limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA content, citrate synthase activity, and cytochrome c oxidase activity were not different in the muscle from the 3 limb populations. However, the ratio of citrate synthase to cytochrome c oxidase was higher in the worse- versus less-affected limbs of PAD patients.

Conclusions: The present study demonstrates a large increase in the frequency of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aging / pathology
  • Citrate (si)-Synthase / genetics
  • DNA Mutational Analysis
  • DNA, Mitochondrial / analysis*
  • Electron Transport Complex IV / genetics
  • Energy Metabolism
  • Gene Deletion
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Intermittent Claudication / genetics
  • Intermittent Claudication / metabolism
  • Male
  • Middle Aged
  • Mitochondria / enzymology
  • Mitochondria / genetics
  • Muscle, Skeletal / blood supply
  • Muscle, Skeletal / enzymology*
  • Peripheral Vascular Diseases / genetics*
  • Peripheral Vascular Diseases / metabolism*


  • DNA, Mitochondrial
  • Electron Transport Complex IV
  • Citrate (si)-Synthase