Chronic Limb-Threatening Ischemia Shows No Adaptability of Mitochondrial Function After Revascularisation

Peripheral arterial disease (PAD) impairs limb perfusion, leading to myopathy characterised by altered mitochondrial content and respiration. Because ischemic muscle appears to adapt differently across PAD stages, we examined stage-specific skeletal-muscle mitochondrial function before and after successful revascularisation. Muscle biopsies of gastrocnemius and vastus lateralis muscle were obtained from 32 patients-21 with intermittent claudication (IC) and 11 with chronic limb-threatening ischemia (CLTI)-before and 6 weeks after successful revascularisation. Mitochondrial respiration was assessed by high resolution respirometry (HRR). HRR results were normalised to citrate synthase activity (CSA) as a marker of mitochondrial content. Inter-individual variation was expressed as the gastrocnemius-to-vastus respiration ratio ('GV ratio'). In the IC group, CSA-normalised mitochondrial respiration of gastrocnemius muscle was significantly reduced after revascularisation, paralleled by a significant decline in the GV ratio. In contrast, CLTI patients showed no significant pre- to postoperative change in CSA-normalised respiration or GV ratio, but mitochondrial content significantly improved by revascularisation. Mitochondrial respiration 6 weeks after successful revascularisation adapts only modestly in milder PAD stages such as IC, while more advanced stages (CLTI) display no functional adaptations. These findings suggest that mitochondrial adaptive capacity is stage-dependent and may require targeted therapeutic strategies beyond revascularisation alone, especially in CLTI.