Peripheral artery disease (PAD) limits limb blood flow and exposes muscle to repeated cycles of ischemia-reperfusion (I/R), leading to chronic oxidative stress, mitochondrial dysfunction, inflammation, and impaired mobility. Traditional supervised exercise therapy (SET) to claudication improves walking capacity but is highly dependent on pain tolerance to ischemia, which lead to highly heterogeneous treatment responses and poor adherence. Muscle oxygen-guided SET approach (M-SET) using near-infrared spectroscopy (NIRS) to titrate workload and avoid excessive ischemia, may elicit more robust immunometabolic stimuli. PURPOSE: To determine whether an acute M-SET session provide a stronger immunometabolic stimulus in circulating immune cells compared with traditional SET in PAD. METHODS: In a randomized crossover pilot, eight patients with PAD (68.8 ± 7.7 years) completed two treadmill sessions: (1) SET, walking to severe claudication before resting, and (2) M-SET, pausing walking when calf StO2 fell 15% below baseline and resuming after recovery. Each session lasted 50 minutes including rests. Blood samples (10 mL) were collected before and after exercise. Peripheral blood mononuclear cells (PBMCs) were isolated, counted and assessed for mitochondrial respiration via high-resolution respirometry. RESULTS: SET (n = 8) did not significantly alter PBMC respiration or cell counts. In contrast, M-SET (n = 6) significantly decreased maximal ADP stimulated complex I+II respiration (11.3 ± 2.6 vs. 10.6 ± 1.5 amol·s-1·cell-1, p < 0.05), complex II specific respiration (7.6 ± 2.1 vs. 6.4 ± 1.7 amol·s-1·cell-1, p < 0.05), and Leak respiration (2.1 ± 0.5 vs. 1.5 ± 0.7 amol·s-1·cell-1, p < 0.05). Notably, the respiratory control ratio (complex I+II state 3 / Leak) was significantly increased after M-SET (5.7 ± 0.8 vs. 7.8 ± 2.0, p < 0.05), which suggested improved coupling between respiration and ATP synthesis. Complex IV specific respiration was not significantly changed in both conditions (SET: 64.4 ± 11.3 vs. 71.0 ± 15.7, p = 0.12; M-SET: 66.8 ± 11.7 vs. 75.0 ± 28.5 amol·s-1·cell-1, p = 0.58). CONCLUSION: M-SET acutely impaired PBMC mitochondrial respiratory capacity, partially compensated by an improved mitochondrial efficiency. The transient defect in PBMC mitochondrial function using oxygen-guided exercise suggest a stronger metabolic stimulus than SET that may optimized immunometabolic adaptation in PAD and initiate more potent long-term mitochondrial adaptations. This work was funded by the Veterans Affairs Office of Research and Development (5I21RX004632-02). This abstract was presented at the American Physiology Summit 2026 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.
Jang et al. (Fri,) studied this question.