Effects Of Exercise Training On Mitochondrial Function In A Large-animal Model Of Peripheral Artery Disease

Abstract

PURPOSE: Our group has developed an endovascular porcine model of ischemic myopathy from peripheral artery disease (PAD). Herein, we tested the hypothesis that mitochondrial dysfunction and oxidative stress are attenuated by exercise training in this model. METHODS: Seven Yorkshire swine were exposed to acute right hindlimb ischemia (HLI) by endovascular external iliac artery occlusion. The swine were randomly separated into two groups: exercise trained (ET) (n = 4) and sedentary control (SED) (n = 3). Exercise training consisted of a structured exercise therapy program on a treadmill (GoPet USA- Model PR730) three days per week, starting 1 week prior to HLI induction and continuing for four weeks after HLI. Speed was increased weekly as tolerated by 1 km/h up to 3.5 km/h with a constant incline of 5%. Food lure was used to motivate animals to participate for as long as tolerated. The session was terminated when the animal reached severe fatigue preventing further exercise. SED animals were exposed to HLI with no ET (regular activity). After termination, mitochondrial respiration, and reactive oxygen species (ROS) production in permeabilized gastrocnemius fiber bundles were simultaneously measured by high-resolution respirometry. RESULTS: After training, the oxygen consumption rate was significantly increased in ischemic muscles, compared to SED during Complex III (CIII) respiration (ET: 14.92 ± 2.82; SED: 5.80 ± 2.26 pmols/sec/mg protein, p < 0.0001) and Complex IV (CIV) (ET: 39.16 ± 3.77; SED: 12.16 ± 1.40, p < 0.0001 pmols/sec/mg protein). In addition, ROS production was significantly attenuated after ET during CIII (ET: 3.21 ± 1.62; SED: 7.10 ± 0.94 pmols/s*ml, p < 0.0001) and CIV (ET: 4.14 ± 0.57; SED: 16.10 ± 0.44 pmols/s*ml, p < 0.0001). CONCLUSION: These data suggest that exercise therapy, which has established efficacy in PAD, is also effective in this new model. Thus, this model may be useful for testing therapeutics targeting the pathophysiological mechanisms of mitochondrial dysfunction and oxidative stress in PAD.