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


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.
Bhat
H K
HK
Department of Medicine, Harbor-UCLA Medical Center, Torrance, Calif. 90509, USA.
Hiatt
W R
WR
Hoppel
C L
CL
Brass
E P
EP
D000368:Aged; D000375:Aging / Q000473:pathology; D002950:Citrate (si)-Synthase / Q000235:genetics; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000032:analysis*; D003576:Electron Transport Complex IV / Q000235:genetics; D004734:Energy Metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007383:Intermittent Claudication / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics; D018482:Muscle, Skeletal / Q000098:blood supply / Q000201:enzymology*; D016491:Peripheral Vascular Diseases / Q000235:genetics* / Q000378:metabolism*