INTRINSIC EXERCISE CAPACITY ON HIND LIMB ARTERIAL LIGATION: DIFFERENTIAL IMPACT OF ACTIVE EXERCISE AND ANDROGEN SIGNALING ON POST-ISCHEMIC RECOVERY
Zakari, Madaniah Omar
Peripheral arterial disease (PAD) is a common disease that is frequently caused by atherosclerosis and associated thrombosis, leading to a decrease in the blood supply to the lower extremities. PAD has various treatment options due to different physiological responses in each patient. One such option includes exercise therapy, since it benefits patients with intermittent claudication by improving their overall quality of life. However, advising exercise therapy for treatment of PAD is not clearly supported, due to the heterogeneity of responses and outcomes found in the scientific literature. This heterogeneous response elaborates the importance of assessing the differential changes resulted from the interaction of active exercise capacity with PAD between high and low intrinsic aerobic capacity phenotypes. High intrinsic aerobic phenotype rat (HCR) reported to have prolonged dopamine availability in the brain. Recently, Dopamine 3 receptor (D3R) was reported to be associated with decrease dopamine reuptake centrally. Despite evidence indicating a role for androgen in dopamine receptors interaction centrally, this interaction remains not studied at the level of skeletal muscle. The overall goal of this dissertation is to determine the vascular adaptive response in relation to active exercise capacity and intrinsic aerobic running capacity phenotypes, HCR and LCR, before and after femoral artery ligation. Additionally, this study will test the hypothesis that exercise after ligation is harmful for the LCR phenotype, while exercise before ligation is protective to ischemic injury, and that post-ischemic repair in skeletal muscle cells (SKMC) associates androgen receptor (AR) and dopamine 3 receptor (D3R) In vivo study: We found that mild exercise intensity after arterial occlusion in rats of low intrinsic aerobic running capacity phenotype (LCR) produces a chronic, ischemia-like vascular adaptive response, with more hypoxia-induced angiogenesis than inflammogenic-induced vasculogenesis. Furthermore, rats of high intrinsic aerobic running capacity phenotype (HCR) showed better muscle-capillary adaptive response to ischemia with more inflammogenic-induced vasculogenesis. However, two weeks of treadmill exercise before femoral arterial ligation was found to precondition the ischemic limb in low intrinsic aerobic running capacity phenotype through remodeling the musculovascular adaptive response. Although, this same procedure did not cause a significant effect in HCR rats. In vitro study: It was found that HCR and LCR have different androgen/dopamine receptor interaction systems, with a stronger protective mechanism in HCR than LCR. In LCR, there is crosstalk between androgen and dopamine receptor signaling during satellite cell proliferation in response to D3R and AR activation respectively. While in HCR, the signaling effect of D3R stimulation does not depend on androgen receptor signaling.
East Carolina University