Regeneration of Mitochondrial Function in Gastrocnemius Muscle in Peripheral Arterial Disease After Successful Revascularisation

Abstract

WHAT THIS PAPER ADDS Affected muscle regions in peripheral arterial disease (PAD) are known to be altered by reduced blood supply. Clinical research projects predominantly deal with the investigation of the underlying atherosclerotic lesions and the development of new technical devices for the treatment of those lesions. The investigation of the lower extremity PAD end organ, namely the muscle, has been neglected so far, and in particular the effect of revascularisation on affected muscle regions has not been evaluated. With this study it could be demonstrated that mitochondrial function in affected muscle regions is able to regenerate after revascularisation. Based on these findings, future studies assessing the clinical correlation between maximum walking distance and mitochondrial respiration could give additional information about underlying pathophysiological mechanism of muscle affected by PAD.Objective: Myopathy, characterised by altered mitochondrial function, is a central part of the pathophysiology of peripheral arterial disease and the aim of this study was to investigate the effect of revascularisation on mitochondrial function. Methods: High resolution respirometry was used to investigate mitochondrial respiration and the results were normalised to citrate synthase activity (CSA), a marker of mitochondrial content. Ten patients with symptomatic peripheral arterial disease (study group) and 10 subjects without ischaemia (control group) were included. Ankle brachial index and ultrasound imaging were performed before and after vascular intervention to confirm technically successful revascularisation. Within the study group, muscle biopsies from the gastrocnemius muscle were taken before vascular intervention and six weeks after revascularisation. Within the control group, tissue was harvested once. Results: There were no significant group differences regarding anthropometric data. CSA showed a significant increase after successful revascularisation (CSA pre-operative 281.4 (252.4e391.8) nmol/min/mg protein vs. CSA post-operative 438.5 (361.4e471.3) nmol/min/mg protein; p ¼ .01) with post-operative return of values to the range of control subjects (CSA control 396.6 (308.2e435.9)). Mitochondrial respiration normalised to CSA in oxidative phosphorylation (P) as well as in electron transfer (E) capacity were significantly reduced post-operatively when compared with pre-operative values (P pre-operative 0.218 (0.196e0.266) pmol/(secÂmg) per CSA vs. post-operative 0.132 (0.116e0.150) pmol/(secÂmg) per CSA, p ¼ .007; E pre-operative 0.230 (0.195e0.279) pmol/(secÂmg) per CSA vs. post-operative 0.129 (0.120e0.154) pmol/(secÂmg) per CSA, p ¼ .005) meaning a post-operative return of values to within the range of control subjects (P control 0.124 (0.080e0.155) pmol/(secÂmg) per CSA; E control 0.121 (0.079e0.125) pmol/(secÂmg) per CSA).Conclusion: With these results, it has been shown that the initially impaired mitochondrial function and content can normalise after revascularisation.

The effect of revascularization on recovery of mitochondrial respiration in peripheral artery disease: a case control study

“…Patients’ characteristics including presence of cardiovascular risk factors are given in Table 1 . Detailed information about the clinical stage of PAD, morphology of SFA lesions and performed vascular interventions have been described earlier [ 10 ] and are shown in detail in Additional file 1 : Table S1.…”

“…With the titration of 5 mM pyruvate and 10 mM succinate, CI&II-linked respiration yields oxidative phosphorylation (OXPHOS) capacity ( P ). Stepwise addition (0.05 mM steps) of the protonophore carbonyl cyanide p-(triflouromethoxy) phenylhydrazone (FCCP) yields maximum mitochondrial respiration or electron transfer ( E ) capacity [ 10 ].…”

“…In a previous study, we were able to demonstrate recovery of mitochondrial content and respiration six weeks after successful revascularization of underlying arteriosclerotic lesions. Gastrocnemius muscle biopsies from patients suffering from isolated flow-limiting pathologies of the superficial femoral artery (SFA) and a non-ischemic control group have been investigated by HRR [ 10 ]. Successful revascularization of underlying arteriosclerotic lesions resulted in restoration of blood flow and oxygen supply to the gastrocnemius muscle.…”

Skeletal Muscle Mitochondrial Dysfunction and Oxidative Stress in Peripheral Arterial Disease: A Unifying Mechanism and Therapeutic Target

“…Following this initial publication, this same group examined a larger population (n = 25 PAD and 16 controls) and observed similar findings of decreased mitochondrial respiration, specifically supported by electron transport system complexes I, III, and IV but not II [79]. Recent studies employing a similar methodology for mitochondrial assessments have reported that age-matched control subjects and mild PAD patients with intermittent claudication have similar muscle mitochondrial respiratory function [82,83,86] or even elevated mitochondrial respiratory capacity normalized to either weight or citrate synthase activity [84]. These contrasting findings are likely explained by the clinical characteristics of patients in the studies.…”

“…Data are presented as a percentage of the control group and patients were classified as intermittent claudicants (IC-mild PAD) or chronic limb-threatening ischemia (CLTI-severe PAD) based on the clinical characteristics provided by the authors of each paper. Please refer to the following references for these original studies:[53,[74][75][76][77][78][79][80][81][82][83][84][85][86][87].…”