Real world exposures to physiologically and/or psychologically stressful environments are often multifactorial. For example, high-altitude typically combines exposure to hypobaric hypoxia, solar radiation and cold ambient temperatures, while sea level thermal stress is often combined with supplementary or transient stressors such as rain, solar radiation and wind. In such complex environments, the effect of one stressor on performance may be subject to change, simply due to the presence of another independent stressor. Such differential influences can occur in three basic forms; additive, antagonistic and synergistic, each term defining a fundamental concept of inter-parameter interactions. As well as the natural occurrence of stressors in combination, understanding interactions is fundamental to experimentally modelling how multiple physiological strains integrate in their influence on or regulation of - exercise intensity. In this thesis the current literature on neuromuscular fatigue and the influence of thermal and hypoxic stress is reviewed (Chapter 1). This is followed by an outline of the methodological developments used in the subsequent experiments (Chapter 2). In the first experimental study (Chapter 3) a novel approach was adopted to investigate the combined effect of muscle cooling and hypoxia on neuromuscular fatigue in humans. The results showed that the neuromuscular system s maximal force generating capacity declined by 8.1 and 13.9% during independent cold and hypoxic stress compared to control. Force generation decreased by 21.4% during combined hypoxic-cold compared to control, closely matching the additive value of hypoxia and cold individually (22%). This was also reflected in the measurement of mechanical fatigue (electromechanical ratio), demonstrating an additive response during combined hypoxic-cold. From this study, it was concluded that when moderate hypoxia and cold environmental temperatures are combined during low intensity exercise, the level of fatigue increases additively with no interaction between these stressors. Before conducting a more complex investigation on combined stressors, a better understanding of the role of muscle temperature on central fatigue - i.e. voluntary muscle activation via the afferent signalling pathways was sought. The focus of Chapter 4 was to quantify the relationship between muscle temperature and voluntary muscle activation (central fatigue) across a wide range of temperatures. The primary finding was that different muscle temperatures can induce significant changes in voluntary activation (0.5% reduction per-degree-centigrade increase in muscle temperature) when neural drive is sustained for a prolonged effort (e.g. 120-s); however this effect is not exhibited during efforts that are brief in duration (e.g. 3-s). To further explore this finding, Chapter 5 investigated the effect of metaboreceptive feedback at two different muscle temperatures, using post-exercise muscle ischemia, on voluntary activation of a remote muscle group. The results showed that at the same perceived mental effort, peripheral limb discomfort was significantly higher with increasing muscle temperature (2% increase per-degree-centigrade increase). However any influence of increased muscle temperature on leg muscle metaboreceptive feedback did not appear to inhibit voluntary muscle activation - i.e. central control - of a remote muscle group, as represented by an equal force output and voluntary activation in the thermoneutral, contralateral leg. In Chapter 6, the psycho-sensory effects of changes in muscle temperature on central fatigue during dynamic exercise were investigated. During sustained dynamic exercise, fatigue development appeared to occur at a faster rate in hot muscle (4% increase per-degree-centigrade increase) leading to a nullification of the beneficial effects of increased muscle temperature on peak power output after a period of ~60-s maximal exercise. In support of previous studies using isometric exercise (Chapter 4 and 6), participants reported significantly higher muscular pain and discomfort in hot muscle compared to cooler muscle during dynamic exercise (2 and 1% increase per-degree-centigrade increase respectively), however this did not result in a lower power output. From Chapters 4, 5 and 6 it was concluded that in addition to faster rates of metabolite accumulation due to cardiovascular strain, it is possible that a direct sensitisation of the metaboreceptive group III and IV muscle afferents occurs in warmer muscle. This likely contributes to the reduction in voluntary muscle activation during exercise in the heat, while it may attenuate central fatigue in the cold. It was also interpreted that muscle afferents may have a similar signalling role to cutaneous sensory afferents; the latter of which are recognised for their role in providing thermal feedback to the cognitive-behavioural centres of the brain and aiding exercise regulation under thermal stress. The impact of body core and active muscle temperature on voluntary muscle activation represented a similar ratio (5 to 1 respectively) to the temperature manipulated (single leg) to non-temperature manipulated mass (rest of body) in Chapters 4, 5 and 6. This indicates that voluntary muscle activation may also be regulated based on a central meta-representation of total body heat content i.e. the summed firing rates of all activated thermoreceptors in the brain, skin, muscle, viscera and spine. Building on the initial findings of Chapter 3, Chapter 7 investigated the causative factors behind the expression of different interaction types during exposure to multi-stressor environments. This was achieved by studying the interaction between thermal stress and hypoxia on the rate of peripheral and central fatigue development during a high intensity bout of knee extension exercise to exhaustion. The results showed that during combined exposure to moderate hypoxia and mild cold, the reductions in time to exhaustion were additive of the relative effects of hypoxia and cold independently. This differs from the findings in Chapter 3, in which fatigue was additive of the absolute effects of cold and hypoxia. In contrast, combining moderate hypoxia with severe heat stress resulted in a significant antagonistic interaction on both the absolute and relative reductions in time to exhaustion i.e. the combined effect being significantly less than the sum of the individual effects. Based on the results in Chapter 7, a quantitative paradigm for understanding of systematic integration of multifactorial stressors was proposed. This is, that the interaction type between stressors is influenced by the impact magnitude of the individual stressors effect on exercise capacity, whereby the greater the stressors impact, the greater the probability that one stressor will be cancelled out by the other. This is the first study to experimentally model the overarching principles characterising the presence of simultaneous physiological strains, suggesting multifactorial integration be subject to the worst strain takes precedence when the individual strains are severe.

La faiblesse des muscles périphériques, définie par une diminution de la force maximale volontaire en dehors de tout état de fatigue neuromusculaire, est une complication fréquente de la broncho-pneumopathie chronique obstructive (BPCO). La force maximale volontaire dépend à la fois des propriétés musculaires périphériques (i.e. volume et architecture musculaire, qualités contractiles) et de la capacité du système nerveux à activer le muscle maximalement. Dans la BPCO, plusieurs travaux ont souligné l'existence paradoxale d'une perte de force maximale volontaire sans altérations musculaires périphériques et sans qu'un déficit d'activation volontaire n'ait clairement été identifié. Pourtant, les patients atteints de BPCO présentent de nombreuses altérations du système nerveux, compatibles avec une capacité d'activation volontaire altérée.L'objectif de ce travail de thèse était donc de tester l'implication du système nerveux dans la faiblesse musculaire de la BPCO et d'en déterminer les mécanismes sous-jacents. Au cours de nos travaux, nous avons mis en évidence une activité corticale diminuée dans la BPCO lors de contractions maximales et sous-maximales volontaires. Nous avons par ailleurs rapporté une perte d'excitabilité du cortex moteur et un déficit d'activation volontaire spécifique aux patients atteints de faiblesse musculaire. Ces résultats sont en accord avec une implication des altérations cérébrales dans la faiblesse musculaire périphérique de la BPCO. Nous sommes ensuite parvenus à identifier une origine potentielle des altérations cérébrales : les désaturations en O2 au cours du sommeil avec mouvements non-rapides des yeux (NREM). Cette hypothèse a été corroborée par l'observation d'un niveau d'activation volontaire réduit chez les patients désatureurs en sommeil NREM. En revanche, aucune répercussion significative n'a pu être observée sur la force maximale volontaire de ces patients, suggérant l'existence d'un mécanisme compensatoire. In fine, nos résultats constituent une avancée importante dans la compréhension du phénomène de faiblesse musculaire, classiquement attribué à la seule perte de masse musculaire. L'implication du système nerveux central dans la faiblesse musculaire ouvre notamment la voie à de nouvelles modalités de prise en charge par des approches spécifiques, dans l'optique de lutter contre la faiblesse musculaire et ses multiples répercussions négatives dans la vie du patient atteint de BPCO. / Peripheral muscle weakness, as defined by a reduced voluntary strength outside any state of neuromuscular fatigue, is a common complication of chronic obstructive pulmonary disease (COPD). Maximal voluntary strength is determined by both peripheral muscle properties (i.e. muscle volume and architecture, contractile quality) and the nervous system's ability to activate the muscle maximally. In COPD, many studies highlighted the paradoxical existence of maximal voluntary strength loss without any peripheral muscle impairment, and without a clearly identified voluntary activation deficit. However, patients with COPD exhibited several nervous system alterations compatible with a reduced maximal voluntary activation capacity. The aim of this thesis was to test the nervous system implication in COPD muscle weakness and to determine the involved mechanisms. As major results, we found a reduced cortical activity in COPD during maximal and sub-maximal voluntary contractions. Furthermore, we reported reduced motor cortex excitability and voluntary activation deficit, specifically in patients with muscle weakness. These results are in accordance with an involvement of cortical alterations in COPD muscle weakness. Then, we indentified a potential origin for cortical alterations: O2 desaturation during non-rapid eye movement (NREM) sleep. This hypothesis has been corroborated by the observation of a reduced voluntary activation in patients with NREM sleep desaturation. However, no significant repercussion could have been observed on maximal voluntary strength in these patients, suggesting a compensatory mechanism.Our results are an important step forward in understanding the COPD muscle weakness that was classically attributed to loss of muscle mass only. The involvement of the central nervous system in COPD muscle weakness also brings about new patient care opportunities via tailored approaches, in order to fight against muscle weakness and its deleterious consequences on a patient's life.