Skeletal Muscle Pathology in Peripheral Artery Disease: A Brief Review

Abstract

This brief review summarizes current evidence regarding lower extremity peripheral artery disease (PAD) and lower extremity skeletal muscle pathology. Lower extremity ischemia is associated with reduced calf skeletal muscle area and increased calf muscle fat infiltration and fibrosis on computed tomography or magnetic resonance imaging. Even within the same individual, the leg with more severe ischemia has more adverse calf muscle characteristics than the leg with less severe ischemia. More adverse computed tomography-measured calf muscle characteristics, such as reduced calf muscle density, are associated with higher rates of mobility loss in people with PAD. Calf muscle in people with PAD may also have reduced mitochondrial activity compared with those without PAD, although evidence is inconsistent. Muscle biopsy document increased oxidative stress in PAD. Reduced calf muscle perfusion, impaired mitochondrial activity, and smaller myofibers are associated with greater walking impairment in PAD. Preliminary evidence suggests that calf muscle pathology in PAD may be reversible. In a small uncontrolled trial, revascularization improved both the ankle-brachial index and mitochondrial activity, measured by calf muscle phosphocreatine recovery time. A pilot clinical trial showed that cocoa flavanols increased measures of myofiber health, mitochondrial activity, and capillary density while simultaneously improving 6-minute walk distance in PAD. Calf muscle pathological changes are associated with impaired walking performance in people with PAD, and interventions that both increase calf perfusion and improve calf muscle health are promising therapies to improve walking performance in PAD.

Keywords: ischemia; mitochondria; muscles; peripheral artery disease; reperfusion injury.

Figure 1.. Fiber areas lacking intermyofibrillar mitochondria in gastrocnemius muscle from PAD patients.

A. Histochemistry for succinate dehydrogenase (SDH) and immunohistochemistry (IHC) identifying type I myosin heavy chain (MyHC; pink) showing mitochondrial cavities in type I fibers within the gastrocnemius muscle of a PAD patient. Representative region of interest from an image acquired at 100x magnification. Scale bars = 100 µm. B. SDH and IHC for mitochondrial membrane COX-1 (complex IV; green) and complex I (orange) showing an absence of mitochondria and mitochondrial activity in the center of a gastrocnemius muscle fiber from a PAD patient. Image acquired at 400x magnification. Scale bars = 50 µm.