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The purpose of this dissertation series was to examine oxygen uptake kinetics in skeletal muscle by evaluating responses of local muscle deoxygenation during incremental exercise in healthy individuals using near-infrared spectroscopy (NIRS). Metabolic activity in skeletal muscle, as part of the integrative responses of the cardiovascular, respiratory and neuromuscular systems, are major determinants of an individual’s physical capacity and function. The workings of these systems, called whole-body metabolism, affect the capability of an individual to engage in activities of daily living, to exercise, and participate in athletic performance. Thus, they have a strong impact on health as engagement in physical activity is well known to be effective in improving cardiorespiratory fitness and reducing the risks of chronic disease. At this time, the in vivo relationships between whole-body metabolism and local muscle metabolic activity are not well understood, but with the availability of NIRS technology this is possible. NIRS is a noninvasive optical technique used to continuously measure changes in muscle tissue oxygen saturation locally, allowing interrogation of the functional integration between muscle metabolism and the cardiovascular system in intact human beings, which is what the series of studies in this dissertation evaluate. Healthy adults and adolescents were enrolled as healthy control participants into an observational study evaluating changes in local muscle oxygen uptake in neuromuscular disease during exercise. Participants performed a maximal cardiopulmonary exercise test (CPET) on a recumbent cycle ergometer. Changes in muscle deoxygenation (HHb), reflecting local oxygen uptake, were measured using NIRS and whole-body metabolism was assessed synchronously via expired gas analysis. After an initial increase in HHb at exercise onset, a consistent pattern of plateau in HHb was observed in the healthy participants near the end of peak exercise. Despite increasing workload and oxygen uptake (VO2) in the final minutes of the test, it was unclear what mechanisms were contributing to this HHb response. It was hypothesized that the HHb-Workload relationship evaluated at the time of VO2peak would be non-linear, such that a greater maximum workload achieved at VO2peak would not be linearly matched by greater ΔHHb (i.e., greater total change from rest to VO2peak). First, a critical evaluation of the literature was conducted to explore this hypothesis. Chapter 2 provides the results of a scoping review that was performed in order to better understand the scientific evidence using NIRS that describes the relationships between indices of muscle oxygen saturation and workload during incremental exercise. This formed the basis to pursue the hypothesis-driven research presented in the subsequent chapters, interrogating the overarching question of this dissertation related to the HHb-Workload relationship. The review revealed there are three methodological approaches to examining changes in muscle oxygen saturation and workload, the least common of which was examination of HHb and workload at the VO2peak time point. Changes in muscle oxygen saturation and work have also been studied as the change in muscle oxygenation over the duration of exercise and at a certain time point or intensity during incremental exercise. Based on the literature, it was clear that there was a dearth of research examining the HHb plateau response in relation to work at VO2peak. Accordingly, chapter 3 provides the results of a pilot study that evaluated the relationship between change in HHb (ΔHHb) and the maximum workload (MW) achieved at VO2peak, where it was hypothesized that the relationship at this time point would be non-linear. A polynomial regression model was used to describe the relationship. The results of this study showed that at lower maximum workloads there were initial increases in ΔHHb with increasing maximum workload but at the highest maximum workloads, ΔHHb attenuated. A polynomial model including ΔHHb and MW, with VO2peak (an indicator of cardiorespiratory fitness) as a covariate, best characterized the relationship. Age was not significantly related to ΔHHb or MW, and VO2peak appeared to play a partial role as its inclusion as a covariate helped explain approximately a quarter of the variance, suggesting other factors may be contributing to the attenuated HHb response. From this pilot work it was hypothesized that the attenuation in ΔHHb at higher maximum workloads, and the HHb plateau observed during CPET, could be explained by muscle efficiency. If so, a longer duration and lesser slope of the HHb plateau in the minutes leading up to VO2peak occurs in muscles with higher metabolic efficiency. As muscle efficiency is defined as a ratio of external work accomplished to internal energy expended, the hypothesis, if true, would support a better matching of the internal work (VO2) to the external work (workload on the ergometer). Chapter 4 provides the results of a secondary analysis that sought to determine whether the observed plateau in HHb reflected muscular efficiency by comparing the slope of the HHb plateau (HHb[s]) to a commonly used method of assessing muscle efficiency, delta efficiency (DE). It was hypothesized that HHb[s] and DE would be inversely and significantly correlated, providing a potential mechanism for the attenuated HHb response and a noninvasive method for assessing muscle efficiency. In contrast to the hypothesis, HHb[s] and DE were not associated, suggesting that a mechanism other than muscle efficiency is contributing to the HHb plateau. Collectively, this series of studies demonstrate that there is a need to better understand the relationship between HHb and workload in healthy individuals, because of a paucity of evidence exploring the HHb-MW relationship at VO2peak, the finding that ΔHHb attenuates at higher maximum workloads, and that results suggest the HHb plateau phenomenon cannot be explained by muscle efficiency. Future work should seek to elucidate the mechanism that allows healthy individuals to achieve higher workloads (i.e., continue exercising at high intensity) without further increasing muscle oxygen uptake, in a larger more heterogeneous sample.