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, suggesting that mitochondrial adaptive capacity is stage-dependent.
Key Findings
Results
In intermittent claudication (IC) patients, CSA-normalised mitochondrial respiration of gastrocnemius muscle was significantly reduced after revascularisation.
21 patients had intermittent claudication (IC) and 11 had chronic limb-threatening ischemia (CLTI)
Muscle biopsies were obtained before and 6 weeks after successful revascularisation
The reduction in CSA-normalised mitochondrial respiration was paralleled by a significant decline in the gastrocnemius-to-vastus respiration ratio (GV ratio)
High resolution respirometry (HRR) was used to assess mitochondrial respiration
HRR results were normalised to citrate synthase activity (CSA) as a marker of mitochondrial content
Results
CLTI patients showed no significant pre- to postoperative change in CSA-normalised mitochondrial respiration or GV ratio after revascularisation.
11 patients with chronic limb-threatening ischemia (CLTI) were studied
No significant changes in CSA-normalised respiration were detected 6 weeks after successful revascularisation
No significant change in the gastrocnemius-to-vastus respiration ratio (GV ratio) was observed in CLTI patients
This contrasts with the IC group, which showed significant changes in the same measures
Results
Mitochondrial content, as measured by citrate synthase activity (CSA), significantly improved after revascularisation in CLTI patients.
Citrate synthase activity was used as a marker of mitochondrial content
The improvement in mitochondrial content was specific to the CLTI group
This finding indicates that while mitochondrial quantity responded to restored perfusion in CLTI, mitochondrial function (respiration) did not
Biopsies from both gastrocnemius and vastus lateralis muscles were analyzed
Discussion
Mitochondrial adaptive capacity after revascularisation appears to be stage-dependent, with more advanced PAD stages showing diminished functional adaptability.
IC represents a milder stage of PAD while CLTI represents advanced disease with limb-threatening perfusion impairment
IC patients showed at least modest functional adaptation (significant reduction in CSA-normalised respiration and GV ratio), whereas CLTI patients showed none
The authors suggest that chronic ischemic myopathy in CLTI may impair the muscle's ability to functionally adapt even after perfusion is restored
The study used the GV ratio (gastrocnemius-to-vastus respiration ratio) as a measure of inter-individual variation in mitochondrial function between the ischemic and non-ischemic limb regions
Conclusions
The findings suggest that targeted therapeutic strategies beyond revascularisation alone may be necessary, especially in CLTI patients.
Restoration of blood flow alone was insufficient to recover mitochondrial respiratory function in CLTI patients at 6 weeks
The authors indicate that ischemic muscle adapts differently across PAD stages
The study examined a total of 32 patients (21 IC, 11 CLTI) with biopsies from gastrocnemius and vastus lateralis muscles
The 6-week postoperative time point was chosen to assess early mitochondrial adaptation following successful revascularisation
What This Means
This research suggests that the muscles of patients with severe peripheral artery disease (PAD) — a condition where blocked arteries reduce blood flow to the limbs — do not recover their energy-producing capacity after a procedure to restore blood flow (revascularisation), even when the procedure is successful. The study compared patients with milder PAD (intermittent claudication, causing leg pain when walking) versus those with severe PAD (chronic limb-threatening ischemia, or CLTI, where the limb is at risk of amputation). Muscle biopsies were taken before and six weeks after revascularisation from 32 patients to measure how well the muscle's powerhouses (mitochondria) were functioning.
The results showed a clear difference between the two groups. Patients with milder PAD showed some changes in mitochondrial function after the procedure, indicating at least a modest response to restored blood flow. However, patients with the most severe form of the disease (CLTI) showed no improvement in how well their mitochondria were working, even though the overall number of mitochondria in the muscle did increase. This means that while the muscle started building more mitochondria, those mitochondria were not functioning normally — suggesting the muscle tissue may be too damaged by prolonged ischemia to recover its energy metabolism quickly.
This research suggests that simply fixing the blocked artery may not be enough to restore normal muscle function in the most severely affected patients. Patients with CLTI may need additional treatments — such as exercise rehabilitation or other therapies targeting muscle metabolism — alongside revascularisation to achieve meaningful functional recovery. These findings could help explain why some PAD patients continue to have poor limb function even after technically successful vascular procedures.
Speichinger F, Gratl A, Raude B, Arndt M, Hering N, Greiner A, et al.. (2026). Chronic Limb-Threatening Ischemia Shows No Adaptability of Mitochondrial Function After Revascularisation.. Journal of cellular and molecular medicine. https://doi.org/10.1111/jcmm.71383