Abstract Endurance training commenced with reduced endogenous and exogenous carbohydrate eCHO) availability enhances training-induced oxidative adaptations of skeletal muscle. However training with reduced endogenous CHO has been shown to compromise absolute training intensity. Additionally, contractile-induced protein degradation and synthesis is increased and decreased, respectively, to a greater extent when exercise is commenced with reduced glycogen availability, compared to when the same exercise is commenced with normal muscle glycogen content. Taken together, chronic exposure to endurance training with low muscle glycogen availability could not only result in a de- training effect due to an inability to maintain high absolute workloads, this approach to training could also lead to a progressive loss of lean muscle mass. There is accumulating data to suggest that protein provision before during and after endurance exercise (EE) enhances post-exercise skeletal muscle protein synthesis as well as activation of signalling molecules regulating translation initiation and elongation. Furthermore, there is evidence that the consumption of branched-chain amino acids during exercise improves exercise performance and reduces perceptions of effort during exercise undertaken in a glycogen depleted state. This thesis investigated the effects of protein ingestion before, during and after exercise commenced with reduced eRO availability on exercise capacity and cell signalling responses associated with the regulation of mitochondrial biogenesis and muscle protein synthesis. It was anticipated that the findings obtained from this research would provide practical nutritional implications to combat the proposed negative effects associated with commencing EE with reduced eHO availability. In a fully randomised cross-over design separated by 7-10 days, ten participants reported to the laboratory on the evening before each trial to perform a glycogen depleting bout of intermittent exhaustive cycling. The following morning, participants arrived at the laboratory in a fasted state and performed 45 rnin of steady-state cycling at 50% peak power output (PPO) and a subsequent bout of intermittent exhaustive cycling at 40 and 80 % PPO as a measure of exercise capacity. Subjects ingested protein (PRO) or placebo (PLA) before (1 L), during (500 ml) and after exercise (1 L). Muscle biopsies were sampled from'the vastus lateralis immediately before and after exercise, and also 3 hours after exercise. Followinz the completion of the 45 min steady-state cvclinz protocol. -- '" ." '-" .1 ' ·f i "' r • i ! 1 there was no difference in time to exhaustion (P = 0.61) between trials during the subsequent exercise capacity test (24.7 ± 10.2 and 25.6 ± 8.7 mm for placebo and protein, respectively). Phosphorylation of AMPKThr172 increased by approximately 3-4 fold post- exercise (P = 0.03) with no difference (P = 0.545) between trials and returned to basal levels at 3 h post-exercise. In contrast, exercise did not alter phosphorylation of p38MAPKThrlSO/TYrlS2 (P = 0.54) or total protein content of POC-la at any time-point post-exercise (P = 0.77). Although not statistically significant (P = 0.09), our results illustrate a physiological trend for greater dephosphorylation of eEF2 Th66 (i.e. activation) in the protein trial post-exercise and at 3 h post-exercise, implying greater signalling for protein synthesis to occur in this trial. Whilst the present thesis provides further evidence that protein supplementation enriched with BCAAs does not improve exercise capacity in a glycogen depleted state, we do provide novel data implicating that protein ingestion may prove beneficial during low CHO endurance training. We demonstrate that protein ingestion before, during and after exercise still allows for activation of cell signalling pathways associated with regulating mitochondrial biogenesis in response to exercise commenced with reduced muscle glycogen availability. Additionally, we have shown that under identical conditions, protein ingestion before, during and after EE enhances the activation of eEF2, a proxy marker of muscle protein synthesis, therefore providing efficacy for use of protein supplementation as a nutritional strategy to combat the evident increased and decreased protein degradation and synthesis, respectively, during low CHO EE.

Ageing refers to a multidimensional process of physical, psychological, and social change of an organism over time. As life expectancy increases the prevalence of ageing related diseases raises. Thus, it becomes essential to distinguish the contributions to health and disease of ageing per se and lifestyle. It is well established that increased physical activity can protect against metabolic diseases and reduce mortality. However, methods of inducing a durable increase in daily physical activity are not well established and there are particular difficulties in bringing about long term changes in behaviour. The interaction of physical activity with ageing is complex. It remains to be shown how much physical activity can modify age related sarcopenia. The work described in this thesis aimed to answer basic questions about motivation to exercise, effects of exercise and the interaction of physical activity and maintenance of muscle mass. The first study was conducted in order to determine the effect of physical activity and ageing upon body composition and mediators of glucose control. Liver lipid, skeletal muscle mitochondrial function, body composition, and metabolism were studied in different ages and physical activity levels. The main research questions were: 1. Does maintaining a physically active vs. sedentary lifestyle produce a different ageing phenotype? 2. Can these differences be characterised using non-invasive biomarkers? This cross sectional study raised awareness on the body composition changes with age which are affected by physical activity level. Additionally, metabolic consequences of ageing were examined and distinguished from those of deconditioning. Magnetic resonance analysis showed a decrease in mitochondrial function with ageing and an increase in liver fat, which was accompanied by insulin resistance. The second study evaluated whether goal orientated exercise advice held benefits for adherence, physical fitness and metabolic flexibility over non-Goal orientated advice in sedentary people. The data demonstrated the critically important factor of sustainability in an exercise program. Maintenance of the exercise regime was enhanced by a goal orientated exercise programme. Exercise alone did not produce a reduction in mean body mass even though compliance was good and physical fitness improved. This holds implications for patients and clinicians. Goal Orientated exercise focussed on mass participation exercise also produced greater metabolic adaptations than standard exercise advice alone. A sub analysis of the data aimed to assess whether increased physical activity had a beneficial effect on all people irrespectively of their ability to lose weight during an exercise intervention. Participants were divided into two groups according to their ability to lose body fat with exercise (Responders group and non-Responders group). The data showed that increased physical activity regardless of weight or fat loss can increase aerobic fitness at all ages with potential beneficial effect on quality of life, disease risk and reduction in mortality. Overall, this thesis describes new information on bringing about change in physical activity and the relationships between age, physical activity and sarcopenia.

Physical inactivity is a primary risk factor for most chronic diseases and accounts for many deaths worldwide. Physical inactivity predisposes towards exercise intolerance, which is the strongest predictor of mortality in health and disease. The ability to sustain exercise is predominantly determined by the ability of the body to transport and utilize oxygen, however the pathophysiology of exercise intolerance remains poorly understood. The current thesis described four experimental studies to investigate the plasticity of oxygen uptake (\/02) and skeletal muscle microvascular oxygenation dynamics under the conditions of health, disease, prior exercise, and hypoxia, in an attempt to better understand the control and limitation of aerobic energy transfer during exercise and its association with exercise intolerance. The initial study developed the first clinical assessment of chronic heart failure (CHF) patients that was able to delineate between attainment of the peak and maximum \/02, The nature of the test design, incorporating prior high-intensity exercise, further revealed that a large subset of patients were able to increase peak \/02 acutely, and this may represent a novel therapeutic target in CHF. To better understand the aetiology of this effect, a moderate-intensity warm- up exercise intervention was used, and revealed two subsets of CHF patients: those in whom \/02 kinetics were limited by a microvascular oxygen delivery and those in whom an intramuscular pathology of oxygen utilization was implicated: the latter being associated with greater disease severity. In vi addition, this study revealed a transient dynamic overshoot in microvascular deoxygenation during exercise - common to CHF - was ameliorated by prior activity, and this was associated with speeded \/02 kinetics. These findings were mirrored in healthy humans, where progressive reductions in oxygen delivery were associated with a lower microvascular oxygenation. These studies confirmed for the first time in humans that the transient microvascular deoxygenation can limit \/02 kinetics. Impairments to skeletal muscle oxygenation therefore likely contribute to the pathophysiology of exercise intolerance demonstrated in health and disease. The final study focused on intramuscular mechanisms that slow \/02 kinetics in health. This study confirmed \/02 kinetics were slowed when exercise was initiated from a raised moderate-intensity work rate, but this was consequent to the raised metabolic rate per se. A reduced intracellular energetic state in the active muscle fibres was implicated to be the mechanism slowing \/02 kinetics during the transient. Overall, the in vivo and in silico evidence collected here has provided new insight into the physiology and pathophysiology underpinning the dynamics of aerobic energy transfer during exercise and its association with exercise intolerance in health and disease. The experiments presented are expected to form the basis of novel therapeutic strategies that may help ameliorate pathological symptoms in CHF and other disease states characterized by exercise intolerance.

This thesis examined relationships between the composition of ingested solutions and nutrient availability in humans.  The rate of fluid and energy availability from an ingested solution depends upon both gastric emptying (GE) and intestinal absorption processes. Experimental results demonstrated that the GE rate of fluid in resting man was significantly delayed by ingestion of ≥6.4 carbohydrate (CHO) solutions, but not by a dilute 2% CHO solution.  Conversely, the rate of energy delivery to the intestine was highest for ≥6.4% CHO solutions.  Solution osmolality had no influence on the GE rate of a 6.4% CHO solution. Relative field uptake rates for 0, 2 and 6.4% CHO solutions were also examined using a ²H technique in resting humans.  Although fluid uptake rates were statistically similar for these solutions, the results suggested a trend for the 2% CHO solution to promote the highest rate of fluid uptake. Lastly, the effect of glucose concentration on cycling capacity under temperate conditions was examined.  Endurance-trained subjects ingested 0 (i.e. water), 2, 4 or 6% glucose solutions during separate 90 min cycles at ~70% VO₂ peak, before cycling to exhaustion at 95% VO₂ peak.  In comparison with the 0% glucose solution, cycling capacity was significantly improved by the 4% glucose solution only.  There was no clear explanation for this result, but it was suggested that improved fluid availability and central function may be partly responsible.

The aim of the present series of studies was to investigate the effect of sodium acetate ingestion on energy metabolism with particular emphasis upon changes in fat and carbohydrate utilisation at rest and during exercise. Ingestion of sodium acetate at rest reduced fat oxidation by 30% over a 90 min period post-ingestion assuming that 90% of the ingested organic acid was oxidised during this time. The decrease in fat utilisation was found to be almost entirely accounted for by oxidation of the exogenous acetate such that carbohydrate utilisation was unaffected.  Plasma glycerol concentration was unchanged following ingestion of the sodium salt, suggesting that the suppression in fat metabolism following acetate ingestion was not due to reduced lipid availability and may have been located intracellularly.  Through the use of stable isotope techniques it was subsequently shown that 80% of the ingested bolus was oxidised over 180 min post-ingestion when sodium acetate was ingested at a dose of 2 mmol.kg^-1 body mass.  Fat utilisation was found to be significantly lower over this period compared to ingestion of a similar dose of sodium bicarbonate (18.43 ± 7.12 vs. 13.85 ± 4.69 g in the bicarbonate and acetate trials, respectively; P < 0.05), with no difference in carbohydrate utilisation between trials. Despite acetate being shown to have no effect upon carbohydrate utilisation, it was observed in a separate study that acetate ingestion improved glucose tolerance during a 75 g oral glucose tolerance test. Blood glucose and plasma insulin concentration were significantly elevated 15 min after consumption of a glucose load compared with a trial matched on fluid volume, sodium ingested and changes in acid-base balance (bicarbonate ingestion).  Glucose and insulin then decreased at a quicker rate between 30 and 120 min post-ingestion of the glucose load following sodium acetate ingestion.  In a second series of studies the effect of perturbing substrate utilisation at rest on metabolism during subsequent prolonged exercise was examined. Ingestion of sodium acetate at a dose of 4 mmol.kg^-1 body mass was shown to suppress fat oxidation at rest (0.11 ± 0.03 vs. 0.06 ± 0.02 g.min^-1 in the bicarbonate and acetate trials, respectively; P < 0.05) with no effect upon carbohydrate utilisation thus supporting the previous findings.

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