The field of oxygen uptake kinetics has revealed much about both the regulation of cardiovascular adjustments with exercise and of factors of intracellular loci of metabolic control of oxidative phosphorylation. Although comprehensive reviews have discussed the factors controlling the dynamic adjustment of oxygen utilization during exercise in detail (33,36,38), debate remains regarding the key mechanisms controlling the adjustment of oxidative phosphorylation during the exercise on-transient. The prevailing view during the past 15 years has been that oxygen uptake (V˙O2) kinetics in young healthy subjects are controlled mainly by intracellular mechanisms and that O2 provision to the active tissues might play a role in determining the adjustment of oxidative metabolism only in aging or diseased populations (31,32). In opposition to that view, for the past 6 years, we have explored the hypothesis that once an initial “metabolic inertia” is overcome, then the rate of adjustment for oxidative phosphorylation is mainly controlled by O2 availability within the regions of metabolic demand. To that aim, we have published data from a number of studies using different experimental designs and models. These studies have demonstrated that, when the V˙O2 time-constant (τV˙O2) is greater than 20 s, O2 delivery and/or distribution to the tissues plays a critical role in determining the speed of V˙O2 kinetics in older and in young healthy individuals (22,23,25,27,37), and that improvements in the matching of O2 delivery (and/or distribution) to O2 utilization can result in the speeding of V˙O2 kinetics to a τV˙O2 of approximately 20 s.
Thus, the aim of this review is to put forward the view that adequate O2 provision to the active tissues does indeed play a critical role in the dynamic adjustment of oxidative phosphorylation.
NONINVASIVE ESTIMATION OF THE MATCHING OF MUSCLE O2 DELIVERY TO O2 UTILIZATION
Although more invasive procedures have permitted direct measurements of leg blood flow and arterial-venous O2 differences (a-vO2diff) during the exercise on-transient in humans (12), these measurements are not easy to obtain and do not necessarily reflect the dynamic behavior of blood flow and O2 extraction within the microvasculature. In this regard, the use of muscle deoxygenated hemoglobin data ([HHb] indicating the balance between O2 delivery and O2 utilization) derived from near-infrared spectroscopy (NIRS) has allowed for the determination of the dynamic profile of O2 extraction at the microvascular level. Although the NIRS-derived [HHb] signal may be influenced by small arteries and venules and the signal may reflect both vascular and muscle oxygenation as the contribution of myoglobin has not been separated from the hemoglobin, there is technical literature explaining the physics behind the use of the NIRS-derived [HHb] signal as a proxy for the dynamic adjustment O2 extraction, as well as empirical data from other studies using different approaches that justify the use of this signal. For instance, the decreases in the microvascular (18) and intracellular (16) pressure of O2 (PO2) observed in other studies using a “square-wave” change in exercise/stimulation intensity are mirror images of the [HHb] signal commonly observed in humans. Similarly, the profiles of the a-vO2diff in canine (11) and human (12) preparations also have shown striking similarities to that of the [HHb] (see Figure 2 in Grassi et al. (11) for a summary). However, although the use of the dynamic profile of the [HHb] signal can be justified, it has to be acknowledged that the actual O2 content in the arterial and venous circulations remain unknown, so that the actual a-vO2diff within the area of NIRS interrogation cannot be discerned. This concept restricts the possibility of determination of the absolute microvascular blood flow by simply combining V˙O2 and [HHb] data. Previous research attempted to estimate the adjustment of capillary blood flow based on the Fick equation (7), but we have criticized this approach for its lack of consistency (28).
Alternatively, we have proposed the utilization of the normalized [HHb] to the pulmonary V˙O2 (V˙O2p) ratio ([HHb]-to-V˙O2 ratio) for inspection of the dynamic relationship between O2 extraction and O2 utilization during the exercise on-transient so that inferences on the behavior of microvascular O2 delivery (blood flow) can be derived (22,23,25,27,28,37). Briefly, for calculation of the [HHb]-to-V˙O2p ratio during exercise transitions within the moderate-intensity domain, the second-by-second [HHb] and V˙O2p data are normalized for each individual (with 0% representing the 20-W baseline value and 100% representing the steady state of the response). This normalization is performed so that the time course of adjustment for both signals ([HHb] and V˙O2p) can be considered independently of the absolute amplitude. In addition, the amplitude of the [HHb] signal varies between individuals independent of the actual amount of O2 extraction (i.e., two subjects exercising at the same absolute moderate intensity, with similar V˙O2 amplitude and likely similar blood flow, might have markedly different amplitudes in the [HHb] signal with increases of, for example, 5 μmol in one subject and 20 μmol in another subject).
The normalized V˙O2p is left shifted by 20 s to account for the phase I–phase II transition, making the onset of exercise coincide with the onset of phase II V˙O2p (26), which reflects muscle V˙O2 (V˙O2m) within 10% (12). Data are then further averaged into 5-s bins for statistical comparison of the rate of adjustment for [HHb] and V˙O2p. In addition, an overall [HHb]-to-V˙O2 ratio is derived for each individual as the average value from 20 to 120 s into the transition. A value of 1.0 for this ratio represents a “perfectly” matched dynamic adjustment of the [HHb] and V˙O2 signals (i.e., [HHb]-to-V˙O2 ratio during the on-transient reveals an O2 delivery to O2 utilization similar to that witnessed in the steady state), whereas values higher than 1.0 represent a transient progressive inequality in the dynamic profile of each signal so that [HHb] adjusts more rapidly than V˙O2, thus suggesting a mismatch between O2 delivery and O2 utilization in the area of inspection. The results from this procedure are depicted in Figure 1. Two main limitations characterize this approach: 1) phase II V˙O2p data are used to reflect V˙O2m; 2) V˙O2p data are left shifted by 20 s to account for the phase I–phase II transition. This is a rather conservative approach to avoid overestimation of the overshoot in the [HHb]-to-V˙O2 ratio. Limitations to this methodology have been addressed in detail elsewhere (27). Although it is acknowledged that this ratio does not provide a measure of blood flow as derived from rearrangement of the parameters in the Fick equation, it is accepted that a faster rate of adjustment of normalized [HHb] compared with the normalized V˙O2p (i.e., greater reliance on O2 extraction–deoxygenation to achieve a given V˙O2) inexorably implies a transient limitation in tissue O2 distribution so that inequalities in the matching of O2 delivery to O2 utilization can be derived. Because absolute changes in [HHb] do not reflect the absolute changes in a-vO2diff, changes in [HHb] cannot be used as a replacement for a-vO2diff in the Fick equation as this mass balance equation would be disrupted (for details on this issue, the reader is referred to Murias et al. (28)). Keeping that in consideration, plotting the V˙O2/[HHb] ratio would result in a response that mirrors the [HHb]-to-V˙O2 ratio.
EFFECTS OF EXERCISE TRAINING ON O2 DELIVERY AND V˙O2 KINETICS
Exercise training interventions had been shown to result in speeding of V˙O2 kinetics in both older (1) and young (3) individuals. However, the mechanisms controlling this faster adjustment in the rate of oxidative phosphorylation and the time course of this adjustment remained unclear. To that extent, we designed a 12-week endurance exercise training protocol (three times per week, 45 min per session, cycling at a power output that would elicit approximately 70% of the maximal V˙O2 (V˙O2max)) that included reevaluation of the τV˙O2p response (representing the time required to reach 63% of the total increase in V˙O2) and V˙O2max every 3 weeks. In those studies, we demonstrated a reduced τV˙O2p (i.e., the rate of adjustment of oxidative phosphorylation was significantly faster) after the exercise training intervention in both older and young women (22) as well as older and young men (23). All the changes in V˙O2 kinetics occurred within the first 3 weeks of training, despite further changes in V˙O2max throughout the training program. Importantly, the changes in the τV˙O2p observed through the endurance exercise training were highly correlated to the changes in the [HHb]-to-V˙O2 ratio (r values ranging from 0.93 to 0.98; Fig. 2A) so that the smaller the ratio (indicating a better matching of O2 delivery to O2 utilization), the faster the V˙O2 kinetics response. Indeed, during those studies, we observed that the young individuals, who speeded their V˙O2 kinetics from approximately 30 to 35 s to approximately 20 s, significantly reduced the [HHb]-to-V˙O2 ratio from approximately 1.15 to approximately 1.0 (Fig. 2A–C). However, the older individuals only could speed their V˙O2 kinetics from approximately 45 s to approximately 33 s and reduce their [HHb]-to-V˙O2 ratio from approximately 1.25 to approximately 1.15 (Fig. 2A, D). We interpret this differential response to reflect structural limitations within the vasculature of the elderly that cannot be overcome by a short-term exercise training intervention. For instance, although the exercise training intervention might have been successful at improving endothelium-dependent responses, as previously described (14), longer periods of exercise might be needed to induce vasculature remodeling so that further improvements in vascular responsiveness, and thus O2 delivery, can be obtained.
An interesting observation from these studies was that improvements in the matching of O2 delivery to O2 utilization could speed the V˙O2 kinetics response up to approximately 20 s. However, no further speeding was possible. In this regard, it could be that impairments in O2 delivery cause an additive increase in τV˙O2 beyond that imposed by the fundamental intracellular limitation that controls the initial phase of the V˙O2 adjustment (likely to be largely regulated by creatine kinase (CK)-catalyzed phosphocreatine (PCr) hydrolysis (13)). As such, the “tipping point” defining an O2 delivery-dependent and -independent zone proposed by others (32,34) could reside in that approximately 20-s area. Notably, this tipping point would not be limited necessarily to older (34) or diseased populations (32), but it also could be observed in young healthy individuals.
DOES O2 DELIVERY PLAY A ROLE IN THE ADJUSTMENT OF V˙O2 IN YOUNG HEALTHY INDIVIDUALS?
Based on the results from our training studies, we proposed to further investigate if O2 provision to the active tissues, as determined from the interaction between the dynamic responses of the normalized [HHb] and V˙O2p signals, could play a role in determining the rate of adjustment of oxidative phosphorylation in young healthy individuals. To that end, three different experiments were conducted.
[HHb]-to-V˙O2 Ratio in Subjects With Differing τV˙O2 Kinetics
The goal of this study was to compare the rate of adjustment of the [HHb] and V˙O2 signals in young healthy individuals and to determine if interindividual variation in V˙O2 kinetics in this population could be related to a mismatch between O2 delivery and O2 utilization to the active tissues. Subjects were grouped based on τV˙O2p into these four subgroups: very fast (VF), τV˙O2p less than 21 s; fast (F), τV˙O2p 21 to 30s; moderately fast (M), τV˙O2p 31 to 40 s; slow (S), greater than 40 s. The [HHb]-to-V˙O2p ratio displayed a progressively larger transient “overshoot” relative to the subsequent steady state level in the F (1.05 ± 0.04), M (1.09 ± 0.04), and S (1.22 ± 0.09) groups compared with the VF (0.98 ± 0.04) group (no “overshoot”). A positive correlation between the [HHb]-to-V˙O2p ratio and τV˙O2p was observed (r = 0.91; P < 0.05) (Fig. 3). Two main conclusions were derived from this study: 1) Young healthy adults, typically associated with having fast V˙O2 kinetics responses, displayed a wide range of τV˙O2p values (including a group with particularly large values (41–70 s)); 2) The slower V˙O2 kinetics in these groups of healthy young individuals were associated with a mismatch between O2 delivery and O2 distribution, as reflected by progressively greater [HHb]-to-V˙O2 ratios in the subjects displaying V˙O2 kinetics responses ranging from very fast to slow, respectively (27).
Mod-Hvy-Mod Exercise Model
For this study, the relationship between the adjustment of [HHb] and phase II τV˙O2p during moderate-intensity exercise was examined before (Mod 1) and after (Mod 2) a bout of heavy-intensity priming exercise (Hvy) in a group of young healthy men. This model has been shown to result in Mod 2 displaying faster V˙O2 kinetics compared with Mod 1 because of the effect of priming exercise augmenting local blood flow and/or increasing the activity of the “metabolic machinery” before Mod 2 (15). It was hypothesized that, if local muscle O2 availability somehow limits the rate of adjustment of V˙O2p at the onset of moderate-intensity exercise, reductions in τV˙O2p during Mod 2 should be accompanied by reductions in the [HHb]-to-V˙O2 ratio (i.e., closer to 1.0). The results from this study (25) showed that τV˙O2p was reduced in Mod 2 (21.7 ± 4.6 s) compared with Mod1 (28.0 ± 9.4 s) (P < 0.05). Similarly, the group [HHb]-to-V˙O2 ratio was closer to unity in Mod 2 (1.01 ± 0.06) compared with Mod 1 (1.08 ± 0.09) (P > 0.05), and there was a significant correlation between the change in τV˙O2p and the change in the [HHb]-to-V˙O2 ratio (r = 0.78; P < 0.05) (Fig. 4, empty circles). These data supported the idea that a better matching of local O2 delivery to O2 utilization was responsible for the smaller τV˙O2p during Mod 2, suggesting again that improved muscle O2 perfusion plays a critical role in determining the rate of adjustment of V˙O2p even in young healthy individuals, at least when τV˙O2p is larger than approximately 20 s. In this regard, it is important to note that not all studies have shown speeding of V˙O2 kinetics after priming exercise in young individuals (4). The main reason for this lack of speeding in V˙O2 kinetics in Mod 2 in some studies could be related to the characteristics of the group being tested. For instance, in Burnley et al. (4), subjects had a τV˙O2p smaller than 20 s before the bout of heavy-intensity priming exercise. Under these conditions, any further speeding of V˙O2 kinetics related to improvements in O2 provision is not to be expected because our data consistently support the idea that improving the matching of O2 delivery to O2 distribution in the active regions eliminates the main constraint to the rate of adjustment of oxidative phosphorylation when τV˙O2p is approximately 20 s. Indeed, Gurd et al. (15) showed that those subjects with larger τV˙O2p values displayed the largest reduction in τV˙O2p. Thus, it seems that the initial τV˙O2p will largely determine whether or not and to what extent the rate of adjustment of V˙O2 is sped in Mod 2 or in response to a given intervention.
Mod-Hvy-Mod With Hypoxia
Although data from the Mod-Hvy-Mod model implied that a faster V˙O2 kinetics in Mod 2 compared with Mod 1 was mainly related to improvement in O2 provision to the active tissues, an intervention that primes factors regulating metabolic substrate provision and/or enzyme activation without simultaneously increasing O2 availability in the active tissues still was required. As such, we repeated the Mod-Hvy-Mod model protocol in both normoxic and hypoxic conditions. By combining the Hvy intervention (which is expected to augment both convective and diffusive O2 delivery) with hypoxia (which is expected to impair O2 delivery by reducing CaO2), factors influencing intracellular control (metabolic substrate provision and/or enzyme activation) essentially can be isolated from those of O2 delivery. Results from this study indicated that τV˙O2p in the unprimed conditions (26 ± 7 s) was reduced during Mod 2 in normoxia (20 ± 5 s) (P < 0.05) but not in Mod 2 under hypoxic conditions (30 ± 8 s) (P > 0.05). The [HHb]-to-V˙O2 ratio showed a modest but significant (i.e., P < 0.05 from 1.0) overshoot in the control condition (1.06 ± 0.04), which was abolished in Mod 2 in normoxia (1.00 ± 0.05; P < 0.05) but persisted in Mod 2 in hypoxia (1.09 ± 0.07; P > 0.05) (gray rhomboids in Fig. 4 show the relationship between the change in [HHb]-to-V˙O2 ratio and the change in τV˙O2p). These data supported our previous findings indicating that the faster V˙O2 kinetics observed after priming exercise was attributable to an improved matching of local O2 delivery to O2 utilization. This observation was further supported by the unaltered adjustment of V˙O2p during Mod 2 in the hypoxia condition, which isolated intracellular control factors from the O2 delivery component. Collectively, this study confirmed that, when τV˙O2p is greater than approximately 20 s, local muscle O2 delivery plays a determining role in the dynamic adjustment of oxidative phosphorylation under control conditions in young healthy humans. Interestingly, when O2 delivery was impaired (i.e., hypoxia without previous exercise), τV˙O2p was increased and the [HHb]-to-V˙O2 ratio tended to be elevated. This finding is in line with those of Goodwin et al. (10), in which the adjustment of V˙O2 was slowed progressively by decreasing the rate of convective O2 delivery in isolated canine muscle; under conditions of spontaneous blood flow kinetics, the mean response time for V˙O2 was 18 ± 4 s.
MISMATCH IN O2 DELIVERY TO O2 UTILIZATION: REASONS AND MECHANISMS FOR IMPROVEMENT
During exercise, adequate provision of O2 to the tissues with increasing metabolic demands is a challenging task in humans. This requires a fine-tuned synchronization of vasoconstriction and vasorelaxation signals that increase blood flow to the active tissues while simultaneously securing O2 provision to vital organs and regulating systemic blood pressure. Although bulk delivery of O2 through the conduit arteries is undeniably important, and conduit arteries closer to the active muscles during locomotion have been shown to be more responsive than those more centrally located (19,21), studies looking at the dynamic response of bulk blood flow during the exercise on-transient have shown that the rate of adjustment of femoral blood flow is as fast as (or even faster than) that of muscle V˙O2 (6). These data suggest that O2 delivery does not play an active role in determining the rate of adjustment of oxidative phosphorylation; however, they do not adequately represent the relationship between O2 delivery and O2 utilization that occurs downstream, within the microcirculation. For instance, blood flow to the active muscles is proportional to its oxidative capacity so that, in animal models, a larger proportion of blood flow is provided to the muscles composed of more oxidative type I fibers and less blood flow is delivered to the more glycolytic ones (29). However, this is not as straightforward in humans, in which blood flow distribution to the more oxidative fibers would be more difficult with a muscle mosaic composed of different fiber types with heterogeneous localization and arrangement of motor units (composed of slow- and fast-twitch fibers) distributed throughout the muscle and no evident coordination of the microvascular units supplying the area. In such a scenario, firing of a motor unit might result in perfusion of more capillaries than those needed to exclusively supply the metabolic demand of the active fibers (8), thus making a perfect matching between O2 delivery and O2 demand a difficult task.
Another factor that plays a critical role in the effective supply of O2 to the active tissues is the responsiveness of the vessel. In this respect, relaxation of the vascular smooth muscle by diffusion of nitric oxide (NO) produced in the endothelial cells through endothelial NO synthase (e-NOS) has been shown to be essential (9). The amplitude and rate of adjustment of the endothelium-dependent vascular vasoresponsiveness has been shown to be greater and faster in conduit vessels supplying the active muscles (femoral) compared with the aorta (19,21) and in smaller arterioles compared with larger arterioles and conduit arteries (35). In addition, endothelium-dependent improvements in vascular responsiveness have been shown to occur in response to acute exercise (21) and chronic exercise training (2,20), and reversal of impaired vasoresponsiveness with exercise training also through improvements in endothelium-dependent mechanisms has been demonstrated in young untrained individuals (5), as well as in aging (2) and diabetic models (20). Taken together, these data indicate that vascular responsiveness varies depending on the functional characteristics of the vessels and is susceptible to a very short as well as to longer-term interventions. This fits with our model showing improvements in O2 provision to the active tissues in different types of interventions ranging from short-term (Mod-Hvy-Mod model) to more long-lasting ones such as training. It is likely that the mechanisms controlling the improved matching of O2 delivery to O2 utilization are not exactly the same in both situations. For instance, the Mod-Hvy-Mod model will depend on rapid endothelium-dependent changes such as faster rate of vasorelaxation and elevated blood flow from the priming exercise, whereas exercise training interventions will rely on improved endothelium-dependent vasorelaxation as well as on improvement in measures of capillarization as we have previously demonstrated (24). However, it seems evident that improved O2 provision to the active tissues plays a critical role in the faster V˙O2 kinetics observed in our studies.
Contrary to this position, a recent study (30) suggested that local blood flow does not determine the adjustment of muscle V˙O2 at the onset of exercise. However, these data should be assessed with caution from a kinetics analysis perspective. For instance, in that study, measurements of blood flow (O2 delivery) and muscle V˙O2 (from the a-vO2diff) were taken at 0, 5, 10, 15, 20, 30, 90, and 210 s into the exercise on-transient. As such, the study design allowed for resolution of the kinetic response during the first 30 s of exercise and justified the conclusion that, during this period of the “onset” of exercise, the blood flow was not limiting. Indeed, this observation is in agreement with our [HHb] data showing a time delay of no increase in O2 extraction for approximately 10 s followed by approximately 15 s before the O2 extraction and the V˙O2 signals intercept. However, no information on the dynamic adjustment of the response is provided between 30 and 90 s into the exercise on-transient (i.e., the time during which the transient overshoot in the [HHb]-to-V˙O2 ratio is observed). In fact, visual inspection of the data presented in that article would suggest that the overall kinetic response for muscle V˙O2 was slower in the experimental condition of reduced blood flow compared with control, which would be in agreement with our data consistently showing greater reliance on O2 extraction for a given V˙O2 in the 30- to 90-s period.
The use of NIRS-derived [HHb] data in the present context has some limitations inherent to the meaningfulness of the actual [HHb] units as well as to the site of NIRS inspection. Issues related to the need for normalization of the [HHb] signal and the uncertainties of what the [HHb] values mean in terms of actual O2 extraction (a-vO2diff) have been explained in detail elsewhere (27,28). In terms of the site of NIRS interrogation, it has to be acknowledged that, although changes in V˙O2p during exercise transitions must mainly reflect the change in metabolic demands from the active muscles, measurements of the [HHb] signal from only the vastus lateralis muscle might pose a limitation to the analysis. In this regard, although we have shown similar profiles of [HHb] in the vastus lateralis and vastus medialis muscles (6), some spatial heterogeneities within different portions of the quadriceps muscle have been suggested (17). In addition, different patterns of muscle activation might be generated depending on the exercise intensity. In these studies, the vastus lateralis was selected because it is the most active muscle during cycling exercise, at least when exercise is performed within the moderate-intensity domain. Issues related to spatial heterogeneities were minimized by paying careful attention to probe placement so that the area of NIRS interrogation was kept consistent within and between subjects. This does not preclude that future studies should consider evaluating the dynamic adjustment of [HHb], and its interaction with V˙O2, in different portions of the quadriceps and/or other muscles involved in cycling exercise.
OVERALL INTERPRETATION AND FUTURE DIRECTIONS
Although the mechanisms controlling the rate of adjustment of oxidative phosphorylation have been a matter of debate for many years, the current prevailing theory is that O2 delivery to the muscles is not a limiting factor, unless testing older individuals or diseased populations. Our data suggest that this is not the case. As such, we put forward the idea that, although there is a component of the V˙O2 dynamic adjustment that is controlled at the intracellular level, there is also a limitation imposed by the mismatch between O2 provision to and O2 utilization from the active fibers. In this model, the first 20 s of the τV˙O2 response is controlled intracellularly (with individual variation). Thereafter, once the initial adjustment dominated by intracellular control is overcome, and under conditions where the rate of O2 delivery to O2 utilization is not “perfectly” matched, different interventions (i.e., Mod-Hvy-Mod, exercise training, etc.) can improve the matching of O2 delivery to the site of metabolic demand so that faster V˙O2 kinetics can be observed. However, improving the matching of O2 delivery to O2 utilization with these interventions is only effective in speeding the τV˙O2 response to approximately 20 s. Thus, our data support the presence of a tipping point beyond which O2 delivery acts as a factor controlling the V˙O2 kinetics response as previously suggested (32,34). We further propose that this tipping point for determination of τV˙O2 occurs at approximately 20 s and is present not only in older or diseased populations but also in young healthy individuals. This idea is summarized in Figure 5.
Interestingly, recent data have shown that inhibition of CK with iodoactetamide infusion in a dog model resulted in V˙O2 kinetics reductions from approximately 17 s to approximately 8 s (13) as CK-catalyzed PCr breakdown slows the rate of increase of oxidative phosphorylation by acting as a spatial and temporal buffer delaying the increase in adenosine diphosphate in the inner membrane of the mitochondria, which is a potent signal for oxidative phosphorylation. In this scenario, where only approximately 5 to 10 s of the rate of adjustment of oxidative phosphorylation seems unexplained, we see two main lines for future directions: 1) Designing experiments (most likely using animal models) that would aim to provide further mechanistic insights elucidating the remainder of the unexplained delay attributable to intracellular mechanism (∼5 to 10 s or less of the adjustment); 2) Experimenting with different types of interventions (such as performing acute bouts of exercise and/or exercise training programs or using nitrate supplementation) that potentially could improve the matching of O2 delivery to O2 utilization so that the part of the V˙O2 kinetic response that can actually be changed is reduced to its minimal expression. From a clinical perspective, continued exploration of this second option is important, especially for those with slow V˙O2 kinetics, in whom exercise tolerance could be reduced because of increased intracellular disturbance associated with energy production derived from nonoxidative sources.
None of the authors have any conflicts of interest to declare. We would like to express our gratitude to Dr. David N. Proctor, Dr. Norman Morris, and Daniel A. Keir for their constructive feedback on this article.
These studies were supported by Natural Sciences and Engineering Research Council of Canada research and equipment grants. Juan M. Murias was supported by a doctoral research scholarship from the Canadian Institutes of Health Research.
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