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

Background-Patients with peripheral arterial disease (PAD) have exercise li mitation due to claudication-limited pain and metabolic alterations in skel etal 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 reflect ed by an increased frequency of a specific 4977-base pair (bp) mtDNA deleti on mutation. Methods and Results-The deletion frequency was quantified in gastrocnemius muscle of 8 patients with unilateral PAD and 10 age-matched control subject s with the use of polymerase chain reaction methodologies. Muscle from the hemodynamically unaffected (less affected) PAD limb showed an 8-fold increa sed deletion frequency and the hemodynamically affected (worse affected) PA D limb had a 17-fold increased deletion frequency compared with muscle from control subjects. The frequency of the 4977-bp deletion in the worse affec ted limb was positively correlated with the age of the patients but not the claudication-limited exercise performance of the patients. Total mtDNA con tent, 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 l ess-affected limbs of PAD patients. Conclusions-The present study demonstrates a large increase in the frequenc y of the mtDNA 4977-bp deletion in patients with PAD but in a distribution not limited to the hemodynamically affected limb.