Impact of aerobic exercise type on blood flow, muscle energy metabolism, and mitochondrial biogenesis in experimental lower extremity artery disease

Abstract

Exercise training (ET) is recommended for lower extremity artery disease (LEAD) management. However, there is still little information on the hemodynamic and metabolic adaptations by skeletal muscle with ET. We examined whether hindlimb perfusion/vascularization and muscle energy metabolism are altered differently by three types of aerobic ET. ApoE −/− mice with LEAD were assigned to one of four groups for 4 weeks: sedentary (SED), forced treadmill running (FTR), voluntary wheel running (VWR), or forced swimming (FS). Voluntary exercise capacity was improved and equally as efficient with FTR and VWR, but remained unchanged with FS. Neither ischemic hindlimb perfusion and oxygenation, nor arteriolar density and mRNA expression of arteriogenicrelated genes differed between groups. 18 FDG PET imaging revealed no difference in the steady-state levels of phosphorylated 18 FDG in ischemic and non-ischemic hindlimb muscle between groups, nor was glycogen content or mRNA and protein expression of glucose metabolism-related genes in ischemic muscle modified. mRNA (but not protein) expression of lipid metabolism-related genes was upregulated across all exercise groups, particularly by non-ischemic muscle. Markers of mitochondrial content (mitochondrial DNA content and citrate synthase activity) as well as mRNA expression of mitochondrial biogenesis-related genes in muscle were not increased with ET. Contrary to FTR and VWR, swimming was ineffective in improving voluntary exercise capacity. The underlying hindlimb hemodynamics or muscle energy metabolism are unable to explain the benefits of running exercise. Lower extremity artery disease (LEAD) is a frequent arterial pathology affecting over 200 million people worldwide 1. It consists in reduced lower limb blood flow and perfusion, secondary to atherosclerotic plaque stenosis or occlusion of lower limbs arteries. The most typical clinical presentation of LEAD in symptomatic patients is intermittent claudication (IC), which is characterized by ischemic muscular cramping in the legs due to inadequate blood flow delivery to exercising muscles. Consequently, LEAD patients with IC present with diminished walking capacity and lower limb function, in addition to muscle atrophy, resulting in diminished quality of life. Interventions aiming at improving walking performance and preventing functional lower limb decline are essential components of the clinical management of LEAD and IC 2,3. According to current international guidelines, the first-line conservative treatment modality for improving walking capacity in IC patients consists in pharmacotherapy and exercise training (ET) 2,3. There is considerable evidence supporting the benefits of ET on walking capacity in LEAD patients. For example, a recent systemic review and meta-analysis demonstrated that ET improves pain-free walking distance and maximal walking distance, by respectively, 82 and 120 m in IC patients 4. Structured walking ET (i.e. supervised exercise program and structured community-or home-based exercise program) i...

Exercise Prior to Lower Extremity Peripheral Artery Disease Improves Endurance Capacity and Hindlimb Blood Flow by Inhibiting Muscle Inflammation

“…At the end of the exercise or sedentary period, mice underwent unilateral iliac artery ligation to induce PAD and hindlimb ischemia as described previously ( 10 , 14 ). After arterial ligation, mice were kept sedentary for either 5 weeks (first set of experiments; n = 22 mice) or 1 week (second set of experiments; n = 16 mice) before euthanasia.…”

“…Tissue perfusion of ischemic and contralateral non-ischemic hindlimbs was evaluated using a laser Doppler Imager (Moor Instruments Ltd, Axminster, England) in anesthetized mice as described earlier ( 10 , 14 ). In brief, five consecutive plantar foot images of hindlimbs were scanned at 30 s intervals for each mouse.…”

“…Muscle sections were also immunostained with a mouse monoclonal α-smooth muscle actin (α-SMA) antibody to identify arterioles as described earlier ( 10 , 14 ). Arteriolar counts were performed manually, and arteriolar density was expressed as number of arterioles per field.…”

“…The procedure was performed as previously described with slight modifications (10,14). Ischemic and contralateral non-ischemic gastrocnemius muscle samples were collected immediately following euthanasia, snap-frozen in liquid nitrogen, and stored at −80 • C. Approximatively 30 mg of muscle tissue were disrupted and homogenized in lysis buffer using the Tissue Lyser LT (Qiagen, Switzerland).…”

“…Exercise training, and in particular regular walking exercise, has also a central role in PAD management based on considerable evidence demonstrating that it provides important benefits in terms of walking performance in PAD patients (4)(5)(6)(7)(8). We and others have also recently reported improved running capacity following exercise training in a mouse model of PAD/hindlimb ischemia (9,10). Although the therapeutic effectiveness of exercise interventions for individuals with established PAD has been widely documented, it remains unknown, whether exercise initiated before the onset of disease could also be a valuable strategy for alleviating disease severity.…”