The ability to sustain muscular exercise is a key determinant of health, quality of life, and mortality. A low tolerance for exercise contributes to a downward spiral of inactivity, which is debilitating in the elderly and an actual cause of many chronic diseases. Therefore, a better understanding of the mechanisms that allow exercise to be sustained is central to our ability to help maintain health, quality of life and promote longevity. Sustaining muscular exercise depends on the body's ability to provide energy through 'oxidative', or aerobic, pathways. These are chemical reactions that synthesise energy through the consumption of oxygen. However, bodily stores of oxygen are very limited so at exercise onset the lungs, heart and muscles must respond in a coordinated fashion to transport oxygen from the atmosphere to where it is used in the active muscles. In healthy individuals the required increases in pulmonary ventilation, cardiac output, muscle blood flow, and muscle oxygen utilisation occur in a well coordinated fashion. However, to achieve this coordination the responses of these systems lag behind the energy demands by about 3 minutes in normal healthy subjects. The kinetics with which oxygen transport and utilisation can respond therefore determines whether or not the body is able meet the energy demands through oxidative pathways. Because demands for activity fluctuate throughout the day (e.g. walking, stair climbing, etc), the response kinetics of energy providing pathways have a significant impact on the ability to carry out the tasks of daily living. It is of considerable concern, therefore, that these response kinetics are very slow in the elderly, and take about twice as long to reach their requirement compared to young individuals. In the elderly therefore there is a greater high reliance on alternative routes of energy provision (termed anaerobic, because they don't consume oxygen). These are detrimental to exercise tolerance because they are related to increased muscle fatigue, shortness of breath and pain. It is perhaps unsurprising, therefore, that physiological systems respond very rapidly in trained athletes. The mechanisms that determine the integrated responses of the pulmonary, circulatory and muscular systems, however, are currently unresolved. The studies in this proposal aim to improve our understanding of the interactions between oxygen delivery to, and utilisation in, the active muscles during the transition from rest to exercise. A better understanding of how these processes work will improve our ability to address the slow oxygen consumption kinetics in the elderly, as well as the optimisation of these processes in elite athletes. The experiments for these studies are organised into three tracks: 1) studies to elucidate how the kinetics of muscle fatigue and oxygen uptake contribute to limiting exercise tolerance in young, elderly and endurance trained subjects; 2) studies to elucidate how rates of aerobic and anaerobic energy provision are distributed throughout the active muscles; and 3) studies to generate a computer model to simulate energy provision and integrated physiological systems integration during exercise over a variety of conditions. All the experiments are made using non-invasive measurements during leg exercise in young (<30 years), elderly (>65 years) or elite endurance trained athletes (volunteers from the Great Britain cycling squad). The outcomes of this project will improve our understanding of how the body responds to the energy demands of physical activity, and how the provision and utilisation of oxygen is optimised to allow high work rates to be sustained. These studies will therefore underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance in humans, and thereby contribute to the maintenance of health, quality of life, and longevity.

Technical Abstract:
The ability to sustain muscular exercise is a key determinant of cardiovascular health, quality of life, and mortality. Exercise tolerance depends on the effective integration of the pulmonary, circulatory and muscular systems to transport and utilise oxygen. The effective integration of these systems dynamics, however, is still poorly understood. It is known that O2 transport and utilisation (VO2) kinetics are fast in endurance trained subjects and slow in the healthy elderly. Slow VO2 kinetics place an increased reliance on energy contributions from anaerobic sources that contribute to fatigue, dyspnoea and pain and thereby limit exercise tolerance. The purpose of this project is to develop a computational model to explain integrated dynamics of the pulmonary, circulatory and muscular systems across the continuum of healthy human biology. To facilitate this we will study cardiopulmonary and neuromuscular dynamics in healthy young, elderly and endurance trained subjects. Specifically we will investigate the relationship between the parameters of the power-duration curve (determining exercise tolerance) and VO2 kinetics (determining aerobic energy provision) using breath-by-breath gas exchange and instantaneous measurements muscle fatigue during dynamic exercise. In addition, we will measure the heterogeneity of regional muscle oxygenation, metabolism and recruitment using simultaneous near-infrared spectroscopy, magnetic resonance spectroscopy and imaging during exercise to the limit of tolerance. These data will be used to generate a systems biology framework to better understand energy provision during exercise over a variety of conditions. The findings from these studies will underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance, and thereby contribute to the maintenance of health, quality of life, and longevity.

Potential Impact:
In line with the mission statement of The American College of Sports Medicine (of which Dr Rossiter is a Fellow), this collaborative research group is committed to promoting and integrating scientific research, education, and practical applications of exercise sciences to maintain and enhance physical performance, fitness, health, and quality of life. This commitment includes achieving impact through increasing knowledge and scientific advancement, communication, public engagement in health issues, contributing to healthcare policy, advancing UK Sport, and developing the research team. Our group has a good track record of knowledge exchange and impact activities, which will be continued during the proposed programme. For example, we are active in pursuing opportunities for public engagement in our research findings, and have given public lectures on exercise physiology both nationally and internationally. We contribute to knowledge transfer in the local community through the University of Leeds Centre for Health Enterprise, and run education and demonstration days on cardiopulmonary exercise testing for local high-school students. Our group has been involved in the public lecture series of the University of Leeds' 'Olympic Programme' since its outset in 2008, which aims to stimulate excellence, international awareness and engagement within the University and its external stakeholders. The nature of our research means that we are well placed to take advantage of the public interest in specific sporting events (The Oxford and Cambridge Boat Race, for example) to encapsulate the significance of some of our research and publicise findings via the national press (e.g. The Daily Telegraph, 2006; The Daily Mail, 2007). Given the broad implications and appeal of the proposed research (incorporating Olympic athletes and elderly subjects), we envisage this route of knowledge exchange will be particularly fruitful. These activities will be facilitated by our relationship with The University of Leeds press office a Leeds-based public relations company (CampusPR). The impact activities for the collaborative group will be run through the University of Leeds, but each member of the collaborative team will contribute toward their own strengths. Dr Kemp and Dr Benson will contribute to the scientific dissemination of the research through presentations and conferences, and Dr Kemp will access the support of the University of Liverpool, Department of Corporate Communications. Matt Parker from British Cycling will contribute to impact and knowledge transfer through University and public engagement activities based around Olympism (e.g. to University undergraduates, and within the 'Olympic Programme'). The post-graduate and post-doctoral members of the group will maintain the website for the study, which will outline the main aims and findings of our work, and assist with demonstrations and public engagement. We do not envisage direct commercially exploitable information to be gained from this work, however, we do expect to provide direct benefit to UK Sport. The relevant findings will be disseminated to athletes and coaches via oral presentation, in order to better understand the integrated physiology of exercise and benefit training specificity. We also aim accrue information to better understand exercise in the elderly and these findings will be disseminated to stakeholders via public presentations and our ongoing collaborations with clinical colleagues in the NHS (in musculoskeletal, anaesthesiology, cardiology, respiratory, and elderly care specialties). These activities would allow any relevant and/or serendipitous findings to be quickly translated to clinical trial and practice. Through these various activities we aim to heighten awareness of the principles of exercise physiology to have long-term impact on health, quality of life and longevity.