Skeletal muscle metabolism as a target for drug therapy in peripheral arterial disease

Peripheral arterial disease (PAD) is an atherosclerotic disease which modifies lower extremity hemodynamics. There is considerable evidence that skeletal muscle metabolism is altered in PAD. Several studies have demonstrated altered mitochondrial enzyme content in PAD muscle as compared with controls, and enzyme activity may not increase normally in PAD with exercise training. A variety of metabolic intermediates, including acylcarnitines, accumulate in muscle of PAD patients, suggesting incomplete oxidative metabolism. Studies employing 31P-NMR (nuclear magnetic resonance) also suggest a metabolic myopathy in PAD. Strikingly, while hemodynamics do not predict claudication-limited performance, metabolic injury as evidenced by acylcarnitine accumulation is strongly correlated with patients' functional status in PAD. Further, exercise rehabilitation improves claudication-limited performance without modifying large vessel hemodynamics. The stress placed on skeletal muscle during exercise in PAD and the observed evidence of metabolic dysfunction is similar to ischemia/reperfusion injury in cardiac muscle. Recognition of the role of cellular metabolic injury and function in PAD has formed the basis for novel therapeutic strategies in this disease.