Utilizing the oxygen cascade to understand the biology of exercise

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Exercise is a powerful physiological stressor that can be utilized to address questions of basic biology. Similarly, hypoxia also provides a potent physiological stimulus and can be combined with exercise to significantly stress biological systems. The `oxygen cascade' describes the physiological processes permitting environmental oxygen to be delivered and used by working muscle and is fundamental to basic biology. Determining the specific role of each aspect and/or the `limiting step' in the oxygen cascade and how it influences exercise has been a long-standing question for animal and human physiologists. The LONG-TERM OBJECTIVE of my research program is to understand the mechanisms of oxygen transport and utilization under physiologically relevant conditions of exercise and hypoxia. The overarching approach of my program is to study conductance of oxygen (ventilation, pulmonary, cardiac and muscle) and their interaction. Over the next 5 years, my SHORT-TERM RESEARCH OBJECTIVE is to investigate the interaction between the oxygen cascade and exercise by using three distinct but inter-related aims. Each aim will utilize either natural (Aim 1 & 3) or pharmacologically-induced (Aim 2) variations in human anatomy and physiology and investigate the resultant effects on oxygen conductance and the integrative exercise response. Aim 1: To exploit the known sex-differences in airway anatomy and gas exchange to better understand how the pulmonary system limits oxygen transport and utilization during exercise. Aim 2 will use a pharmacological approach to manipulate blood gas homeostasis and determine how this contributes skeletal muscle force production and exercise tolerance in normoxia and hypoxia. Aim 3: Will utilize humans with naturally altered hemoglobin affinity to determine the interaction between oxyhemoglobin affinity and the oxygen cascade during exercise and acute hypoxia. The aims are linked by manipulation of the oxygen cascade, but through different mechanisms. By utilizing different manipulations my research program can probe each aspect of the oxygen cascade in isolation or combined to study integrative human physiology. Overall my research program will seek to identify the role of each `step' in the oxygen cascade during exercise by using novel methods and integrative experimental approaches. Each aim is designed to ensure significant training opportunity for undergraduate and graduate HQP.