The ability to sustain muscular exercise is a key determinant of health, quality of life, and mortality. Poor exercise tolerance contributes to a downward spiral of inactivity, which is debilitating in the healthy elderly and is described by The Centers of Disease Control, USA, as 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 the longevity. Sustaining muscular exercise depends in large part upon the provision of energy through 'oxidative' pathways. These are pathways that synthesise energy in the muscles through the consumption of oxygen. Therefore, the function of the body's systems that transport oxygen from the atmosphere to where it is utilised in the mitochondria of the active muscles, and the ability of the mitochondria to use the oxygen that they receive, is crucial to the ability to sustain high work rates. It is also significant that most conditions of physical activity are 'non-steady state'; that is, the demands for muscular oxygen consumption are not constant, but are continually changing as activity levels are altered. As such, it is the kinetics with which the oxygen transport and utilisation systems can respond that determine whether the body is able meet the energy demands through oxidative means. Rapid response kinetics, therefore, are a characteristic of the effective integration of these physiological systems: Highly trained endurance athletes have fast response kinetics. It is of considerable concern, however, that the response kinetics of oxygen consumption in the elderly are very slow - about twice as slow as young people, and four times slower than in endurance-trained subjects. The mechanisms that determine these response kinetics, however, in health, training, or the elderly are currently unresolved. The studies in this proposal aim to elucidate 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, which contribute to the reduced exercise tolerance in this group. It is not possible to control (experimentally) all the physiological systems that contribute to determining oxygen consumption kinetics in human volunteers. I have, therefore, designed and validated a new experimental technique to achieve this in a rat model of exercise. Rats are an ideal model in this regard: their muscles are similar to those of large human locomotor muscles (such as the muscles of legs); and they manifest similar adaptations to those seen in humans during endurance training and ageing. They also represent an important refinement of the current state-of-the-art, because this type of study is typically made in dogs. Using this new model then, oxygen delivery to skeletal muscles can be controlled via a pump, and key 'oxidative' chemical reactions in the muscles can be controlled (either activated or inhibited) by delivery of drugs. The information provided from this project will benefit the health and quality of life of society by improving our understanding of how the cardiovascular and skeletal muscular systems integrate to allow exercise to be sustained. These novel findings will establish the mechanisms that control oxygen consumption kinetics in healthy animals, and determine how endurance exercise training alters these to bring about improvements in oxygen consumption kinetics. They will also determine how ageing affects the control of oxygen consumption kinetics. These studies will therefore underpin the development of new strategies (either pharmacological or exercise based) for ameliorating the mechanisms limiting exercise tolerance in humans.

Technical Abstract:
Rapid response kinetics are a major feature of an effectively functioning physiological control system. This is exemplified at the onset of muscular exercise where tolerance is highly dependent on the ability to transport and utilize oxygen (O2) at rates corresponding to the demands of the task. However, the mechanisms that determine the response kinetics of muscle O2 consumption (VO2) are poorly understood. Furthermore, it is well appreciated that VO2 kinetics are considerably slower in elderly than in young or exercise trained subjects. These slow VO2 kinetics place increased reliance on energy contributions from anaerobic sources that result in build-up of fatigue-inducing metabolites, and contribute to limiting exercise tolerance. Slow VO2 kinetics therefore predispose the elderly towards premature fatigue and impair quality-of-life. Control of VO2 kinetics during exercise resides within some combination of the processes of O2 delivery, substrate (NADH) and phosphate (ADP) provision, and the activity of the enzymatic systems involved in oxidative phosphorylation. To elucidate the control of VO2 kinetics, therefore, I have designed and validated a novel in situ experimental model allow muscle O2 consumption kinetics to be determined across the stimulated hindlimb of the rat. Convective O2 delivery is controlled via pump perfusion, NDAH and ADP supply are controlled by pharmacological interventions, and enzyme activity can be modulated by age, training and/or pharmacological inhibition. Thus, I will initially determine the flux control of VO2 kinetics in situ in young rat muscle, and then ascertain how ageing and exercise training act of modulate this control. These studies will also investigate how the cardiovascular (O2 delivery) and skeletal muscular (O2 utilisation) systems interact to determine VO2 response dynamics. The findings from this project will underpin the development of ameliorative strategies to overcome the slow VO2 kinetics in the elderly.