Abstract
Whether and how moderate exercise might allow for accelerated limb recovery in chronic critical limb ischemia (CLI) remains to be determined. Chronic CLI was surgically induced in mice, and the effect of moderate exercise (training five times per week over a 3-week period) was investigated. Tissue damages and functional scores were assessed on the 4th, 6th, 10th, 20th, and 30th day after surgery. Mice were sacrificed 48 h after the last exercise session in order to assess muscle structure, mitochondrial respiration, calcium retention capacity, oxidative stress and transcript levels of genes encoding proteins controlling mitochondrial functions (PGC1α, PGC1β, NRF1) and anti-oxidant defenses markers (SOD1, SOD2, catalase). CLI resulted in tissue damages and impaired functional scores. Mitochondrial respiration and calcium retention capacity were decreased in the ischemic limb of the non-exercised group (Vmax = 7.11 ± 1.14 vs. 9.86 ± 0.86 mmol 02/min/g dw, p < 0.001; CRC = 7.01 ± 0.97 vs. 11.96 ± 0.92 microM/mg dw, p < 0.001, respectively). Moderate exercise reduced tissue damages, improved functional scores, and restored mitochondrial respiration and calcium retention capacity in the ischemic limb (Vmax = 9.75 ± 1.00 vs. 9.82 ± 0.68 mmol 02/min/g dw; CRC = 11.36 ± 1.33 vs. 12.01 ± 1.24 microM/mg dw, respectively). Exercise also enhanced the transcript levels of PGC1α, PGC1β, NRF1, as well as SOD1, SOD2, and catalase. Moderate exercise restores mitochondrial respiration and calcium retention capacity, and it has beneficial functional effects in chronic CLI, likely by stimulating reactive oxygen species-induced biogenesis and anti-oxidant defenses. These data support further development of exercise therapy even in advanced peripheral arterial disease.
Highlights
Peripheral arterial disease (PAD) is linked to stenosis or occlusion of the arteries that are responsible for decreased perfusion of the lower limbs
Significant increases in reactive oxygen species (ROS) production are generally considered to be deleterious because it induces lipid peroxidation, protein carbonylation, and mitochondrial dysfunction that in turn is associated with reduced ATP production (Lejay et al, 2014)
The key findings of this study are that moderate exercise, which slightly increases oxidative stress, might allow for shorter time for limb recovery, probably by restoring functional capacities, mitochondrial function and calcium retention capacity in the setting of critical limb ischemia (CLI)
Summary
Peripheral arterial disease (PAD) is linked to stenosis or occlusion of the arteries that are responsible for decreased perfusion of the lower limbs. Oxidative stress, which precedes mitochondrial dysfunction, arises during ischemia, and is enhanced after reperfusion (Guillot et al, 2014). This suggests that modulating ROS production may reduce ischemia-reperfusion injury. Significant increases in ROS production are generally considered to be deleterious because it induces lipid peroxidation, protein carbonylation, and mitochondrial dysfunction that in turn is associated with reduced ATP production (Lejay et al, 2014). Mitochondria are largely involved in PAD pathophysiology and they are considered as a therapeutic target in CLI (Ryan et al, 2015; Paradis et al, 2016)
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