| Description |
The purpose of this dissertation was to investigate the integration of cardiac, skeletal, and vascular smooth muscle in the process of oxygen (O2) transport and utilization. The goal of the first study was to examine the vasomotor function of human skeletal muscle feed arteries (SMFAs), utilizing pressure myography, with a focus on the impact of age. In this study, we demonstrated that in response to an increased shear stress, the SMFAs likely contribute to the regulation of vascular resistance/conductance in vivo. Furthermore, aging likely blunts the capacity to delivery O2 due to reduced endothelial function in these SMFAs identified by attenuated kinetics of vasodilation and maximum vasodilatory capacity. Additionally, this attenuated vascular function was associated with a reduction in the shear-induced activation of eNOS, and elevated free radical production in SMFAs with age. The second study using normal healthy donor hearts (HdH) as a reference, sought to examine the impact of heart failure (HF) etiology on mitochondrial function in the pathology. Specifically, this study examined cardiac muscle mitochondrial function and free radical production in patients with ischemic HF (iHF) in comparison to that of patients with non-ischemic HF (niHF). Both mitochondrial quality and quantity were compromised in HF compared to HdH. Interestingly, a lower tissue mass-specific oxidative phosphorylation (OXPHOS) capacity was documented in iHF compared to niHF, which was predominantly due to reduced mitochondrial content. However, increased non-phosphorylating respiration, and elevated mitochondrial-derived free radical production, as well as an attenuated efficiency of OXPHOS in iHF compared to niHF, suggests an etiology specific reduction in intrinsic mitochondrial function in iHF. Therefore, this study identified HF etiology as an important contributor to the functional abnormalities associated with HF. The third study examined the characteristics and respiratory function of mitochondria in cardiac, skeletal, and vascular smooth muscle. Tissue specific mitochondrial OXPHOS normalized by citrate synthase activity (CSA) was similar in cardiac, skeletal, and smooth muscle; however, there were significant muscle specific differences in both non-phosphorylating respiration and efficiency of OXPHOS. These findings suggest that different muscle tissues have distinct intrinsic mitochondrial function which may influence the efficiency of OXPHOS and potentially free radical production. In summary, this set of studies has identified novel mechanisms underlying blunted O2 supply and utilization often associated with aging and disease in humans. |
