Ischemic preconditioning specifically restores complexes I and II activities of the mitochondrial respiratory chain in ischemic skeletal muscle

ObjectiveDefective mitochondrial function has been reported in patients presenting with peripheral arterial disease, suggesting it might be an important underlying mechanism responsible for increased morbidity and mortality. We therefore determined the effects of prolonged ischemia on energetic skeletal muscle and investigated whether ischemic preconditioning might improve impaired electron transport chain and oxidative phosphorylation in ischemic skeletal muscle.MethodsThirty rats were divided in three groups: the control group (sham, n = 9) underwent 5 hours of general anesthesia without any ischemia, the ischemia–reperfusion (IR) group (n = 11) underwent 5 hours ischemia induced by a rubber band tourniquet applied on the left root of the hind limb, and in the third group, preconditioning (PC group, n = 10) was performed just before IR and consisted of three cycles of 10 minutes of ischemia, followed by 10 minutes reperfusion. Maximal oxidative capacities (Vmax) of the gastrocnemius muscle and complexes I, II, and IV of the mitochondrial respiratory chain were determined using glutamate-malate (Vmax), succinate (Vs), and N, N, N,′N′-tetramethyl-p-phenylenediamine dihydrochloride ascorbate as substrates.ResultsPhysiologic characteristics were similar in the three groups. Ischemia reduced Vmax by 43% (4.5 ± 0.4 vs 7.9 ± 0.5 μmol O2/(min  ·  g dry weight), P < .01) and Vs by 55% (2.9 ± 0.3 vs 6.3 ± 0.4 μmol O2/min/g dry weight; P < .01) in the IR and sham groups, respectively, and impairments of mitochondrial complexes I and II activities were evident. Of interest was that preconditioning prevented ischemia-induced mitochondrial dysfunction. Both Vmax and Vs were significantly higher in the PC rats than in IR rats (+32% and +41%, respectively; P < .05), and were not different from sham values.ConclusionsIschemic preconditioning counteracted ischemia-induced impairments of mitochondrial complexes I and II. These data support that ischemic preconditioning might be an interesting approach to reduce muscular injuries in the setting of ischemic vascular diseases.

Clinical RelevanceThe results of our experimental study showing protective effects of ischemic preconditioning on ischemia-induced damage to mitochondrial complexes I and II is likely to be pertinent in humans. Indeed, acute and chronic ischemia has been shown to induce mitochondrial dysfunctions in human skeletal muscles. Furthermore, consistent experimental data support that mitochondrial activity enhancement results in an enhanced exercise capacity, suggesting that an improvement in skeletal muscle mitochondrial function secondary to ischemic preconditioning might be clinically interesting in patients with peripheral artery disease. Ischemic preconditioning might therefore be useful to protect muscle function in the setting of relatively long periods of ischemia as observed in complex thoracoabdominal aortic reconstructions, or in cases of vascular trauma, with a problem of flap tissue transfer as seen during reconstructive surgery. Overcoming the fact that ischemic preconditioning might sometimes be difficult to directly apply on the vessels and territories concerned by the surgical procedure, remote ischemic preconditioning might be a new therapeutic approach in patients with peripheral arterial disease and critical limb ischemia.