Structured Exercise Therapy Increases Endogenous Antioxidants to Repair Muscle Strength and Health in Porcine Ischemic Myopathy Model of Peripheral Artery Disease

<b>Objective:</b> The mechanisms of structured exercise therapy (SET) in peripheral artery disease (PAD) are not clear. We have developed an SET module for our large animal model of ischemic myopathy. We hypothesized that SET would increase muscle strength and walking distance in this model. The objective was to discover the SET-dependent mechanisms involved in this process. <b>Approach:</b> After induction of unilateral hind limb ischemia, three animals were exposed to standard environmental enrichment (sedentary or SED) and four animals underwent SET thrice weekly for 4 weeks postoperatively. Walking, hind limb pressure indices, and strength testing were performed weekly. Terminal muscle samples were used for skeletal muscle testing. <b>Results:</b> SET animals increased walking distance over time. SET increased muscle strength in both the ischemic and nonischemic limb. When comparing the ischemic SED hind limb muscle with that of ischemic + SET, the SET group has improved respiration and decreased oxidative stress. Markers of cell death and impaired functional regeneration were increased in SED ischemic muscles but returned toward baseline in the SET ischemic muscle. <b>Innovation:</b> This study uses a validated, large animal model of ischemic myopathy similar to that seen in humans with PAD. The effects of exercise on limb function, strength, and skeletal muscle health are reported in this model. <b>Conclusion:</b> SET increases muscle strength and regeneration by increasing endogenous antioxidants and mitochondrial respiration, resulting in favorable muscle health despite ongoing ischemia. This model may assist in preclinical testing of PAD therapies designed to improve muscle health.