Adipose-Derived Mesenchymal Stem Cell Therapy Improves Skeletal Muscle Mitochondrial Function in a Porcine Model of Peripheral Artery Disease

Introduction: Peripheral artery disease (PAD) is an atherosclerotic condition that impairs blood flow to the lower extremities, resulting in mitochondrial myopathy in the affected leg muscles and significant walking impairment. Previous studies using a porcine model of PAD have shown that injection of adipose-derived mesenchymal stem cells (ADMSC) around the aortic trifurcation in the pelvis improves ischemic limb hemodynamics and walking performance. However, the effect of ADMSC treatment on skeletal muscle mitochondrial function remains unknown. Hypothesis: We hypothesized that ADMSC injection around the aortic trifurcation in the pelvis improves skeletal muscle mitochondrial function in a swine model of PAD. Methods: Ten Ossabaw miniswine (age 6 months) with metabolic syndrome were used. Right hindlimb ischemia was induced at week 0 (T0) by coil occlusion of the right external iliac, superficial femoral, and popliteal arteries via carotid artery access. At week 4 (T4), ADMSC (20 x 106 cells) were isolated using stromal vascular fractionation of autologous abdominal wall fat. Using jugular vein access, a catheter with a retractable side-deploying needle was inserted in the right iliac vein. The needle was deployed to access the retroperitoneum, and ADMSC (N=5) or vehicle (N=5) were infused around the aortic trifurcation. Gastrocnemius samples from the ischemic hindlimb were obtained at T4 (before treatment) and week 8 (T8, 4 weeks after treatment) to assess mitochondrial function using high resolution respirometry. Results: ADMSC treatment significantly increased mitochondrial respiration at T8 compared to T4 in complex I (T8: 27.92 ± 1.96; T4: 20.22 ± 2.01 pmols·s-1·mg-1; p<0.05), complex II (T8: 35.71 ± 1.79; T4: 24.01 ± 2.44 pmols·s-1·mg-1; p<0.05) and complex I+II state 3 (T8: 62.75 ± 3.25; T4: 44.23 ± 4.37 pmols·s-1·mg-1; p<0.05), and state 4 (T8: 22.13 ± 1.16; T4: 16.45 ± 1.3 pmols·s-1·mg-1; p<0.05) in the ischemic hindlimbs of ADMSC-treated swine. Conclusions: Our study, using a clinically relevant porcine model of PAD, similar to humans in size, anatomy, physiology, and comorbidities, demonstrates that ADMSC therapy can effectively improve mitochondrial function in ischemic hindlimbs. These findings suggest that ADMSC may be a promising treatment for mitochondrial myopathy in patients with PAD. Funding sources: R01 AG062198, R01 AG077803, R01 HD106911, P20 GM152301, and the Nebraska Research Initiative This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.