Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease

Lower extremity peripheral artery disease (PAD), characterized by atherosclerotic or thrombotic obstructions of lower extremity arteries, affects nearly 250 million people worldwide.¹ Risk factors for PAD include older age, diabetes, smoking, hypertension, and hyperlipidemia.² In people with PAD, ischemia of the lower extremities during walking activity typically causes pain, tightness, weakness, or other discomfort in the legs and buttocks, impairing the ability to walk even short distances without stopping to rest.³ Lower extremity ischemia is associated with adverse lower extremity skeletal muscle (ie, gastrocnemius) characteristics.^4–16 Compared with people without PAD, those with PAD have greater mitochondrial injury, abundance of fibrosis and oxidative stress in lower extremity skeletal muscle.^4–16 Lower extremity skeletal muscle in people with PAD has an increased proportion of myofibers with central nuclei, suggesting ongoing muscle repair, and reduced muscle mass compared with people without PAD.^8–16 Both increased capillary density and reduced capillary density have been reported in skeletal muscle of people with PAD, compared with those without PAD.^6,12 Some adverse gastrocnemius muscle characteristics, such as reduced muscle mass, smaller myofiber size, fewer inflammatory-associated (ie, CD206-) macrophages, and fewer capillary contacts with type I and type IIa fibers were associated with greater walking impairment and increased rates of mobility loss in people with PAD.^{6–8,15,17,18} Although causal evidence is not available, ischemia-related damage of lower extremity skeletal muscle may exacerbate walking impairment in people with PAD.

Walking exercise is first line therapy for people disabled by lower extremity PAD.¹⁹ Compared with a control group that did not exercise, supervised treadmill exercise interventions improved 6-minute walk distance by a mean of 15 to 35 meters, while effective home-based walking exercise interventions improved 6-minute walk distance by 45 to 55 meters.^20–25 Walking exercise interventions have also improved treadmill walking performance, participant perceived walking ability, and physical activity.^20–25 Thus, even while inducing lower extremity ischemia, walking exercise significantly improved walking performance and other outcomes in patients with PAD. This review summarizes evidence regarding the effects of walking exercise on lower extremity skeletal muscle characteristics in people with PAD without chronic limb threatening ischemia. This review focuses on PAD without chronic limb threatening ischemia because lower extremity muscle characteristics differ substantially between people with PAD without chronic limb threatening ischemia and because walking exercise is typically not recommended for people with chronic limb threatening ischemia.^19,26,27

Evidence of Ischemia-Related Lower Extremity Skeletal Muscle Abnormalities in PAD

Atherosclerotic obstructions in the lower extremities restrict delivery of oxygen and nutrients during walking exercise. While direct measurement of ischemia within lower extremity skeletal muscle during walking activity in people with PAD is not typically feasible, evidence for ischemic damage of lower extremity skeletal muscle related to walking includes the following. First, people with PAD typically report lower extremity skeletal muscle discomfort, tightness, weakness, or other adverse leg symptoms during walking activity, when oxygen demand exceeds supply, and these symptoms resolve within minutes of rest, when oxygen supply is sufficient to meet demand.²⁸ Second, in 10 patients with unilateral PAD and 6 patients without PAD, skeletal muscle biopsies showed a higher abundance of short-chain acylcarnitines and lactate in the leg affected by PAD, compared with the contralateral leg without PAD and compared with the patients without PAD, suggesting ineffective oxidative metabolism in ischemic legs of patients with PAD.²⁹ Third, animal models of hindlimb ischemia showed reduced skeletal muscle mass, impaired mitochondrial function, and increased oxidative stress, findings that were also observed in skeletal muscle of patients with PAD.^{4,11–14,30,31}

Overview of Walking Exercise and Lower Extremity Skeletal Muscle in PAD

The fact that walking exercise induces lower extremity ischemia while simultaneously improving walking performance in people with PAD appears paradoxical, since lower extremity ischemia has been associated with lower extremity skeletal muscle pathology in both animals and in humans with PAD.^{4,11–14,30,31} Yet recent evidence supports a hypothesis that the lower extremity ischemia induced by walking exercise may be necessary for improving walking performance in people with PAD. In the LITE (low intensity exercise intervention in PAD) randomized clinical trial, 305 participants with PAD were randomized to ischemic pain inducing high-intensity walking exercise, low-intensity walking exercise without ischemic leg symptoms, or a control group that did not exercise for 12 months.²⁵ While both exercise groups were coached to walk for exercise 5 days per week for up to 30 minutes per session, those randomized to high-intensity exercise walked significantly fewer minutes per week than those randomized to low-intensity exercise (77 versus 145 minutes/wk, P<0.01). Despite fewer minutes of walking exercise, high-intensity ischemic-symptom inducing walking exercise significantly improved 6-minute walk distance, compared with the control group: (between group difference: 49.6 meters (95% CI, 24.3–74.9, P<0.001)) and compared with the low-intensity exercise group (P<0.001). In contrast, the low-intensity exercise group, which walked for exercise at a pace to avoid ischemic leg symptoms, did not improve 6-minute walk more than the control group and declined significantly in walking ability compared with the high-intensity exercise group (between group difference with high intensity exercise group: -40.9 meters, [95% CI -61.7, to -20.0] P<0.001).²⁵ No significant differences were observed in gastrocnemius muscle biopsy measures of citrate synthase activity, cytochrome C oxidase activity, or nitrotyrosine abundance across the 3 exercise groups in the 47 participants who underwent skeletal muscle biopsy at baseline and follow-up.²⁵ While biologic pathways responsible for improved walking performance in response to ischemia-inducing walking exercise, compared with walking exercise without ischemic symptoms, remain unclear in people with PAD, the LITE randomized trial supports the hypothesis that lower extremity ischemia induced by walking exercise may be necessary to stimulate biologic pathways that improve walking performance in people with PAD. In this review, evidence regarding the effects of walking exercise on lower extremity skeletal muscle in PAD is discussed in the context of evidence about the effects of walking exercise on lower extremity skeletal muscle in older people without PAD. While some pathophysiologic changes in lower extremity skeletal muscle of people with PAD may be an extreme version of skeletal muscle changes that occur with aging in people without PAD, the effects of exercise on lower extremity skeletal muscle may differ between older people with and without PAD.