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The determinants of exercise intolerance are vital as they impinge on all individuals and are applicable across the whole spectrum of physical abili.ties. Key in this regard is the rate at which pulmonary oxygen uptake (Vo2 ) adapts to meet the energetic requirement at exercise onset, with this dependent on both the limit (i.e. v02 max) and the contour (i.e. v02 kinetics) of the v02 response. The purpose of this research was. to better understand the mechanisms. controlling v02 kinetics, and also to investigate the mechanisms determining high-intensity exercise tolerance, with specific reference to the hyperbolic power-duration (P-t) relationship. Three studies were conducted: 1. The role of 02 delivery in the control of v02 kinetics during moderate-intensity cycle ergometry. The presence of a delayed increase in deoxygenated [haemoglobin] in the region of muscle interrogation suggests that, during this delay phase, there is a dynamic balance between capillary perfusion and O2 consumption. Hence, it was \. concluded that 02 delivery is not a primary determinant of v02 kinetics, although its potential contribution under certain conditions is acknowledged. 2. Effects of supra-critical power (CP) 'priming' exercise on the profile and parameters of the P-t relationship (i.e. CP and W'J and parameters of aerobic function (i.e. the v02 time constant (rVo2 ), functional gain, lactate threshold (BJ .and Va] maJ during subsequent supra-CP exercise performed to the tolerable limit. 't vo2 , functional gain, SL, CP, v02 max were unaffected, but WI was decreased such that exercise tolerance was reduced as a predictable function of the re-define'd P-t relationship. It was concluded that WI is a key parameter of high-intensity exercise tolerance. 3. The kinetics of w' recovery, relative to ·those of v02 and blood [Lactate]. WI recovery was clearly dissociated both from that of metabolic rate and blood [Lactate], being slower compared to the former but more rapid relative to the latter. Consistent with the results of Chapter 4, exercise tolerance was reduced as a predictable function of the re-defined P-t relationship, supporting the notion that WI 'depletion' shapes high intensity exercise tolerance. Furthermore, doubt is cast on the current view that WI simply reflects a fixed 'store' of energy; rather, accumulation of fatigue-related metabolites instead may be important in defining the physiological constructs ofthis parameter.

Poor exercise tolerance (the inability to sustain physical tasks) is indicative of morbidity, mortality, and low quality of life. The aim of this thesis was to elucidate the determinants of exercise tolerance, which remain incompletely understood. The primary outcome measure was maximal voluntary isokinetic power (Piso), from which locomotor neuromuscular fatigue (exercise-induced reduction in Piso) and 'power reserve' (difference between task power and Piso at intolerance) were quantified. First, a potential association between power reserve magnitude and severity of inspiratory muscle fatigue following short- and long-duration exercise was investigated. Inspiratory rib cage muscle and diaphragm fatigue were inferred from reductions in oesophageal (Poestw) and gastric (Pgatw) twitch pressures, respectively, in response to cervical magnetic stimulation. Global inspiratory muscle fatigue was assessed via transdiaphragmatic pressure (Pditw; difference between Pgatw and Poestw). Inter-trial differences (Δ) in power reserve were not related to ΔPditw (r=-0.47; P=0.17) or ΔPgatw (r=0.53; P=0.11), but were negatively associated with ΔPoestw (r=0.76, P < 0.01), suggesting that a larger power reserve results from a greater contribution to intolerance from rib cage muscle fatigue. Next, whether task power influences locomotor neuromuscular fatigue was assessed. Compared to constant-power exercise, intermittent exercise allows higher powers to be performed without increasing intensity (metabolic stress). Motor unit recruitment and non-oxidative energy provision were greater during intermittent than intensity-matched constant-power exercise (both P < 0.05), but the reduction in Piso was not different between protocols (-13±6% vs. -14±6%, respectively; P=0.69). Finally, adaptations to intensity-matched intermittent and constant-power protocols were investigated. Preliminary findings indicated that traininginduced increases in Piso and V̇O₂peak were not different between protocols (both P > 0.05). However, there was a greater increase in lactate threshold (P=0.02) and 'large' additional increase in exercise tolerance (effect size=2.16) following intermittent compared with constant-power training. Overall, the investigations presented herein may aid optimisation of exercise training strategies to improve exercise tolerance.

Exercise tolerance strongly predicts morbidity and mortality, and correlates with health-related quality of life. The mechanisms underpinning exercise intolerance were investigated in Chapter 3. Peripheral vascular dysfunction occurs when there is an imbalance between endothelial damage and endogenous repair mechanisms, and can contribute to exercise intolerance. Vascular dysfunction typically precedes a diagnosis of cardiovascular disease and is related to disease severity in cardiovascular disease patients (e.g. chronic heart failure; CHF). Exercise training increases vascular function and exercise tolerance in health and CHF, with high-intensity interval training (HIIT) often inducing greater improvements than continuous 'control' protocols. However, it is unknown whether the effectiveness of HIIT can be improved. Therefore, Chapter 4 investigated the acute and chronic effect of HIIT with and without blood flow restriction (BFR) on vascular endogenous repair capacity, ramp-incremental exercise tolerance and V̇O2peak in CHF. Four weeks of HIIT did not induce acute or chronic vascular adaptations; however, chronic HIIT increased ramp-incremental exercise tolerance and V̇O2peak. BFR did not increase training efficacy. Chapter 5 determined whether 6 weeks of HIIT at a high work rate with short work:recovery bouts (intended to maximise the volume of shear rate accumulated) increased vascular endogenous repair capacity, endothelial function, exercise tolerance and V̇O2peak more than intensity-matched continuous exercise training in healthy adults. No acute or chronic vascular adaptations were seen with HIIT. This type of HIIT increased post-training exercise tolerance and V̇O2peak but was no more effective than intensity-matched constant work rate exercise training. Overall, increases in exercise tolerance and V̇O2peak in both training studies were not underpinned by improvements in peripheral vascular endothelial function and/or increases in vascular endogenous repair capacity. Therefore, despite the efficacy of training to increase exercise tolerance, further work is needed to develop exercise strategies that effectively and specifically target improvements in vascular endogenous repair capacity and peripheral vascular function.

Vascular homeostasis is a vital element of health. Exercise plays a role in maintaining the integrity of the vascular endothelium via transient increases in endothelial shear stress that accompany exercise-induced hyperaemia. This hyperaemia and stimulus it presents to the vasculature is governed by exercise intensity. Exercise is the primary therapy in cardiac rehabilitation contexts, a population with typically elevated cardiovascular risk factors and compromised vascular integrity. In the UK, cardiac rehabilitation may be ineffective for improving long-term health outcomes. This thesis demonstrates that the exercise intensities achieved by patients in UK cardiac rehabilitation were variable and generally low. The exercise performed had no impact upon indices of peripheral vascular structure or function and little effect upon short-term health outcomes. A service-level intervention was implemented to increase the dose of exercise achieved by patients via an increase in intensity and examine its effects upon the vasculature. In a subsequent cohort, the intervention was unsuccessful at modifying the exercise intensities that were achieved or indices of peripheral vascular structure or function. However, a positive relationship between the intensity achieved at the end of the programme and changes in vascular function was found. Although peripheral vascular integrity is easily studied it is perhaps less relevant to health compared to central vascular integrity. Assessments of the central circulation during exercise have previously relied upon high-risk, invasive techniques. Therefore, to understand the stimulus presented to the central vasculature by exercise at intensities akin to those achieved in cardiac rehabilitation, a novel technique was applied: using cardiac magnetic resonance imaging during cycling in a healthy cohort. This technique was unable to capture the changes in perfusion of the central circulation that should have occurred with exercise at different intensities but successfully demonstrated reproducible assessments of cardiac dynamics during exercise of different intensities.

Heart failure is a complex clinical syndrome where the heart is unable to maintain adequate cardiac output to meet the metabolic demands of tissues. This leads to a cascade of events that act to impair the oxygen transport system, giving rise to symptoms of fatigue and/or dyspnoea on exertion and, in more severe cases, at rest. Accordingly, exercise intolerance is a cardinal symptom of heart failure, and is a strong predictor of prognosis and mortality. As such, an individual's tolerance to exercise is inextricably linked to diagnosis in heart failure. The mechanisms for this exercise intolerance are still not fully understood and currently there is a debate surrounding whether exercise tolerance is governed primarily by impairments in cardiac function (i.e. oxygen delivery), or impairments at the skeletal muscle level (i.e. oxygen utilisation), or both. Resolving this issue has implications for improving and tailoring effective treatment in heart failure. The work presented in this thesis fulfils two major aims: (i) the development and validation of a computational model of circulatory and oxygen uptake dynamics, that is able to predict oxygen uptake measurements that are experimentally measured at the lungs, and at the skeletal muscle, for ramp incremental exercise and; (ii) the assessment of the clinical utility of using near infrared spectroscopy as a non-invasive tool to determine the locus of exercise intolerance in heart failure patients. The computational model of circulatory and oxygen uptake dynamics demonstrated that cardiopulmonary breath-by-breath gas exchange measurements alone are not sufficient to identify the locus of exercise intolerance in heart failure patients. However, with the addition of a model output that gives specific information on the skeletal muscle oxygenation dynamics, insights into the mechanisms governing exercise tolerance can be gained. Near infrared spectroscopy was utilised under two different experimental conditions. During ramp incremental exercise, it was shown that near infrared spectroscopy can provide specific information regarding the locus of exercise intolerance in heart failure, particularly, those with oxygen delivery limitations. In addition, using a novel technique to assess oxidative capacity, it was established that near infrared spectroscopy can be used to produce reliable assessment of skeletal muscle function and, thereby, proves a promising technique to identify those with skeletal muscle dysfunction.

Introduction: Deterioration in vascular health contributes to cardiovascular disease. Ageing is independently associated with poorer vascular health. Furthermore, the rate of decline in vascular health differs between genders. Exercise-induced shear rate (SR) is hypothesised to be an important stimulus for improvements in vascular health. How interval (IT) and continuous (CON) exercise affect patterns and volumes of SR to modify acute and chronic vascular health across the lifespan and between genders has not been explored. The overall aim of this thesis was to characterise in-exercise SR during IT and CON exercise and assess acute and chronic effect endothelial function and biomarkers of endothelial cell phenotype. Methods: Ultrasound was used to determine acute and chronic endothelial function following exercise and the association with in-exercise SR. Circulating microRNA-21 expression both acutely and chronically was assessed as a biomarker of SR response. Firstly, 13 young healthy participants underwent 4 separate acute exercise sessions consisting of intensity and duration matched CON and IT exercise. Secondly, 16 younger and 11 older (males and females) participants underwent a 4-week training intervention comprising either CON or IT. Results: Pattern of in-exercise SR followed the work rate profile of the exercise. Despite differing SR patterns there was no difference in volumes of anterograde and retrograde SR between protocols, with all exercise protocols inducing retrograde SR and brief periods of purely oscillatory SR, in the first study. Acute endothelial function increased and microRNA-21 expression decreased irrespective of exercise protocol. In the second study, IT induced greater volumes of retrograde SR compared to CON and decreased with training. Endothelial function improved acutely and chronically whilst chronic microRNA-21 expression increased following both IT and CON training irrespective of age or gender. Discussion: In-exercise pattern of SR was driven by heart rate and blood flow. Pattern of SR differed between CON and IT exercise protocols in the second study only. However, all exercise protocols in both studies produced predominantly laminar SR resulting in equivalent improvements in acute and chronic endothelial function, with no influence of age or gender. MicroRNA-21 expression was differentially affected by acute and chronic exercise irrespective of protocol.

Exercise tolerance, the ability to sustain an exercise task, is a key determinant of performance, morbidity, mortality and quality of life. However, the fatigue mechanisms that underpin exercise tolerance remain poorly understood. The aim of this thesis was to determine: 1) the origins of fatigue causing the limit of tolerance (LoT) during whole-body dynamic exercise in which V̇O2max is attained, and 2) how this is altered by the task demands and in the presence of chronic heart failure (CHF). To assess this, maximum voluntary isokinetic cycling power was measured before, during and instantaneously at LoT of exercise, and compared to the task demands. To provide additional insight these power data were supplemented by gas exchange and electromyography measures. First, a series of ramp-incremental exercise tests were performed, using different ramp-incrementation rates to change power demand at LoT. Next, the power-tolerable duration relationship was used to investigate the effect of altering the power demand during constant-power exercise. In both studies, reducing power demands, and as a consequence slowing the rate of energy utilisation and metabolite build-up, caused a significant reserve in maximal voluntary power at LoT to become increasingly evident. A reduced exercise tolerance is a cardinal symptom of CHF, the consequence of fatigue and/or dyspnoeic sensations during exercise. At the LoT in CHF, the magnitude of difference between the maximal voluntary isokinetic power and task demands was different between individuals, suggesting this measurement may distinguish between individuals for which either the exercising muscles, or mechanisms proximal to this, are ultimately limiting exercise. These data demonstrate that the origins of task failure at V̇O2max can be altered, depending on the exercise task and health status. In future it is hoped these data can inform development of targeted strategies, aimed at increasing exercise tolerance, and as a consequence enhancing quality of life.

In comparison to concentric exercise, eccentric exercise allows an individual to achieve high mechanical loads for a lower cardiovascular and metabolic requirement. This highlights it as a possible efficacious rehabilitation intervention for exercise intolerant clinical populations, likely stimulating increases in strength and mobility without the development of exercise limiting symptoms that commonly present during traditional exercise. However, the majority of research utilises unnatural forms of eccentric exercise (i.e. reverse cycling), potentially restricting the compliance and translational benefits. Therefore, we have adapted an eccentric stepping ergometer, that may more closely replicate natural activity, and investigated the acute physiological responses and training adaptations within a young and older adult population. The ergometer adaptations enabled tight control of exercise parameters, and crucially allowed comparison of concentric and eccentric physiological responses on the same device. Consistent with previous literature, we demonstrated a lower eccentric oxygen uptake (V̇O2), heart rate (HR) and blood pressure (BP) at the same power, and a greater eccentric power required to match for concentric metabolic requirement. Interestingly, eccentric V̇O2 and HR progressively increased above a predicted steady state, suggesting a higher exercise intensity at this metabolic rate. Subsequently, we compared concentric and eccentric training within young adults at similar mechanical and metabolic requirements, showing that higher eccentric powers were required to match for concentric V̇O2 and resulted in substantial increases in concentric, eccentric, and isometric strength, not seen with concentric training. Finally, we assessed the feasibility of a short eccentric recumbent stepping programme within an older adult population, showing considerable increases in concentric, eccentric and isometric strength that were maintained at 30-days follow up. Importantly, within both populations, the exercise remained tolerable and resulted in minimal muscle soreness. These results provide further evidence to support the beneficial neuromuscular adaptions of eccentric exercise, and suggest that eccentric recumbent stepping may provide a safer, more tolerable and effective training modality. Pilot studies with additional measures of physiological function (specifically muscle oxidative capacity and fatigue) suggest that eccentric exercise may promote additional benefits beyond those reported in this thesis. It is hoped that the findings from this thesis will eventually contribute to the implementation of eccentric exercise within exercise intolerant populations that stand to benefit most.