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Multi-Scale Model Analysis of O2 Transport and Metabolism: Effects of Hypoxia and Exercise

Zhou, Haiying

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2010, Doctor of Philosophy, Case Western Reserve University, Biomedical Engineering.

To maintain O2 and ATP homeostasis, cardio-respiratory system variables including ventilation and blood flow and muscle tissue O2 consumption are regulated in response to increased energy demand and/or alteration in oxygen supply. In human or animal experimental studies, direct measurements of those control mechanisms are not feasible. To evaluate these mechanisms and physiological processes linking pulmonary to cellular respiration, a “systems bioengineering” approach was applied. This included experimental studies with non-invasive measurements of human subjects and computational models to quantify the relative significance of various factors controlling respiration. The experimental measurements were obtained at two levels: (a) whole body (by indirect calorimetry, bioempedence cardiography); and (b) muscle tissue (by near-infrared spectroscopy).

A multi-organ systems model of O2 and CO2 transport was developed to analyze the control of ventilation and blood flow during hypoxia by comparison with experimental data. Among the aspects of the control processes that this model assessed were possible mechanisms responsible for hypoxic ventilatory decline (HVD). Under isocapnic hypoxia, simulations indicate that HVD can be entirely described by central ventilatory depression and an increase in brain blood flow has no effect on HVD.

The measurements of pulmonary O2 uptake (VO2p) and muscle oxygenation (ΔHbMbO2) were combined with a multi-scale computational model of oxygen transport and muscle cellular metabolism. This model incorporates mechanisms of O2 transport from the airway opening to working muscle, as well as the phosphogenic and oxidative pathways of ATP synthesis in tissue cells. Based on experimental data from healthy subjects, the model simulated responses to a step increase in work rate. The simulations show that VO2p and muscle O2 utilization UO2m have similar characteristic mean response times even though a transit delay exists between tissue cell and the lungs.

In response to a step increase in work rate, the dynamics of muscle oxygenation (ΔHbMbO2) measured by NIRS differs from oxygenation of venous blood (SvO2). To distinguish oxygenated hemoglobin (Hb) and myoglobin (Mb) concentrations from the NIRS signal, a mathematical model of muscle O2 transport and utilization was developed and validated by comparison to experimental data. Simulations of this model, which incorporated changes in muscle microvascular composition during exercise, indicated that Hb and Mb contributions to the NIRS signal are of comparable magnitude. During exercise, the changes in oxygenated Hb and Mb are responsible for different patterns of ΔHbMbO2 and SvO2 dynamics.

The measurements of VO2p and ΔHbMbO2 were also used to evaluate the muscle adaptations to endurance training. The multi-scale model was combined with the changes in muscle microvascular composition to simulate VO2p and ΔHbMbO2 responses to a step increase in work rate. By comparing simulated outputs with experimental data before and after training, optimal estimates of model parameters were obtained that characterize muscle adaptation. These parameter values indicate that training increased the maximal flux rate of oxidative phosphorylation (Vmax) by 53% but did not change significantly the physiological factors related to permeability-surface area (PSm).

Gerald Saidel, PhD (Committee Chair)
Joseph LaManna, PhD (Committee Member)
Kingman Strohl, PhD (Committee Member)
Xin Yu, PhD (Committee Member)
Nicola Lai, PhD (Committee Member)
205 p.

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Citations

  • Zhou, H. (2010). Multi-Scale Model Analysis of O2 Transport and Metabolism: Effects of Hypoxia and Exercise [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1254502393

    APA Style (7th edition)

  • Zhou, Haiying. Multi-Scale Model Analysis of O2 Transport and Metabolism: Effects of Hypoxia and Exercise. 2010. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1254502393.

    MLA Style (8th edition)

  • Zhou, Haiying. "Multi-Scale Model Analysis of O2 Transport and Metabolism: Effects of Hypoxia and Exercise." Doctoral dissertation, Case Western Reserve University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1254502393

    Chicago Manual of Style (17th edition)