Interaction Of Factors Determining Critical Power Part 2

2.2 Diffusive Oxygen Transport

Diffusive O2 transport refers to the diffusive movement of O2 from the capillaries to the muscle mitochondria where O2 serves as the final electron acceptor for the electron transport system. This process is described mathematically via Fick’s law of diffusion:

VO2 = DO2 ( ΔPO2 ) ,

where ̇ VO2 corresponds to the rate of O2 fux, DO2 is the muscle diffusing capacity, and ΔPO2 is the partial pressure difference between the capillary and intra-myocyte spaces (PO2cap and PO2im, respectively). This relationship dictates that elevations in ̇ VO2 must be established via changes in either (1) changes in the driving force for O2 diffusion (i.e.  ΔPO2=PO2cap − PO2im) and/or (2) changes in effective diffusing capacity (i.e. DO2, determined primarily by the aggregate number of blood cells within capillaries adjacent to the myocyte at any given moment [82, 83]).

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Fick’s Law of Diffusion predicts that alterations in FiO2  will bring about concomitant alterations in CP via altered  O2 diffusion in addition to convection. For instance, hypoxia reduces and hyperoxia increases both estimated PO2cap [84] and PO2im [85], though to differing extents such that ∆PO2 is reduced and increased, respectively. Hence, in the studies reviewed in Sect. 2.1 wherein hypoxia reduced [21, 56, 60–62] and hyperoxia increased CP [37, 64, 65], it is also probable that alterations in the transcapillary driving force for O2 fux, and thus diffusive O2 delivery, also contributed  ̇ VO2 = DO2 ( ΔPO2 ), to the alterations in CP observed therein, likely via the alterations this would be expected to have on PO2im [55].

Muscle capillarity is an important influence on DO2, and thus diffusive O2 delivery, as it determines the number of red blood cells adjacent to contracting fibers and thus the surface area available for O2 diffusion. Indeed, Mitchell et al. [86] recently demonstrated a striking relationship between CP and skeletal muscle capillary density (r=0.50), capillary-to-fiber ratio (r=0.88), and capillary contacts per type 1 fiber (r=0.94) in a homogenous group of endurance-trained individuals (63.2±4.1 mL kg−1 min−1, range:  58.7–72.2 mL kg−1 min−1). These findings indicate that enhancements in diffusive O2 fux enable a metabolic steady state to be attained for a greater range of power outputs (i.e. extending the range upwards), thus increasing CP.

Further insight into the role of diffusive factors in determining CP/CF was provided by a series of experiments by Ansdell et al. that compared the power-duration relationship between the sexes during small- [87] and large-muscle mass exercise [88]. It was demonstrated that CF occurred at a greater relative percentage of the MVC in female individuals compared with male individuals during small-muscle mass, intermittent, isometric single-leg knee extension exercise [87]. Conversely, there were no differences observed in the relative percentage of MVC at which CP occurred between male and female individuals during large-muscle mass dynamic cycle exercise [88]. Female individuals have previously been demonstrated to possess a greater degree of capillarity in skeletal muscle and a greater proportion of type I fibers when compared with male individuals [89–91], suggesting a greater capacity for diffusive O2 transport. Moreover, during small-muscle mass knee extension exercise, far greater mass-specific rates of blood flow are achieved when compared with cycle exercise, and hence, diffusive rather than convective factors constrain O2 transport to muscle mitochondria [52, 81, 92–97]. These authors [87, 88] consequently interpreted their findings to indicate that during single-limb exercise where convective factors are not limiting, the sex difference in CF arises because of a greater skeletal muscle diffusive capacity of female individuals [87, 88]. Conversely, during dynamic cycle exercise where muscle O2 delivery is constrained by the central nervous system to prevent a dangerous fall in mean arterial pressure [98], convective O2 delivery may be relatively more important in determining CP than muscle diffusive capacity, leading to the lack of a sex difference in this mode of exercise [87, 88].

Utilizing measurements of brachial artery blood flow via Doppler ultrasound and NIRS to determine muscle O2  extraction, Broxterman et al. [73] were able to estimate muscle ̇ VO2 and thereby estimate the contributions of enhanced convective and diffusive O2 delivery to the changes in CP they observed between 20 and 50% duty cycles (discussed in Convective Oxygen Delivery). These authors demonstrated that the increase in DO2 in the 20% versus the 50% duty cycle was approximately double the increase in convective O2 delivery that occurred between the same trials (i.e.+69% vs+34%, respectively), implicating changes in diffusive, rather than convective, O2 delivery as being a more important determinant of CP in this situation. These authors suggested that the shorter duty cycle would have facilitated higher red blood cell velocity and therefore increased the surface area of the capillary involved in gas exchange (i.e. longitudinal capillary recruitment [99]), thereby enhancing DO2 and contributing to the increased CP. Interestingly, this observation is also consistent with the suppositions of Ansdell et al. [87, 88] noted above, namely that diffusive factors may be more important for constraining CP during small versus large-muscle mass exercise. That DO2 is an independent determinant of CP was recently confirmed by Colburn et al. [100]. Specifically, the vascular ATP-sensitive K+  channel inhibitor glibenclamide decreased CS in rats, and this was accompanied by a 25% decrease in DO2 determined from measurements of skeletal muscle blood flow, arterial O2 content, and interstitial and microvascular O2 pressures [100]. Collectively, therefore, there is now a growing body of evidence to indicate that CP can be influenced by factors dictating the rate of diffusion of O2 from capillaries to mitochondria.

2.3 Oxygen Utilisation

A sentinel parameter defining the skeletal muscle bioenergetics system is the time constant of the fundamental phase of muscle ̇ VO2 kinetics (i.e.  VO2), which is reflective of the time taken to attain 63% of the ̇ VO2 amplitude in response to a change in metabolic demand [101–104], and is closely reflected by the pulmonary VO2 [103]. Pulmonary VO2 is therefore a highly convenient assay of the time course of changes in oxidative phosphorylation that occur at the onset of exercise or during changes in the metabolic rate. At the onset of exercise, therefore, the delayed response of pulmonary and muscle ̇ VO2 kinetics that is encapsulated by the parameter VO2 necessitates an energy deficit that must be met via a reduction in O2 stores and an increased rate of substrate-level phosphorylation [103, 105, 106]. This “O2 deficit” is a function of VO2 and the steady-state increment  ̇ VO2 [105], at least for work rates where a steady state is rapidly attained. The magnitude of this O2 deficit at exercise onset is critical, as it determines (1) the degree of reliance on non-oxidative sources of energy provision (i.e. depletion of [PCr] and [glycogen] and consequent accumulation of [L−] and [H+]), (2) the magnitude of metabolic perturbation incurred during the rest-to-work transition (i.e. Δ[PCr], Δ[ADP], Δ[Pi], extracellular [K+] accumulation, loss of sarcoplasmic Ca2+ release and sensitivity), (3) the extent of fatigue induction sustained and (4) the loss of skeletal muscle efficiency induced during the rest-to-exercise transition [8, 10, 14, 101, 102, 104, 107–110]. ̇ VO2 kinetics would therefore appear to be central in setting the tolerability of exercise. Indeed, very low VO2 values (i.e. fast ̇ VO2 kinetics) are observed in endurance athletes [111] and trained individuals [112], whereas very large VO2 values (i.e. slow ̇ VO2 kinetics) are observed in the elderly [113] and chronically ill [102]. However, until relatively recently, an independent role for VO2 in determining CP had not been considered.

Murgatroyd et al. [14] characterized relationships between VO2 and CP by normalizing exercise intensity across individuals such that the tolerable duration of exercise was uniform (6 min). They demonstrated a strong inverse correlation between VO2 and CP (r=0.95), consistent with the notion that VO2 has an independent role in determining CP. Moreover, when this analysis was extended across human populations spanning the extremes of aerobic function (i.e. healthy young trained individuals, young inactive individuals, healthy elderly individuals, and patients with COPD), the relationship between VO2 and CP was strong, inverse, and linear [104]. These authors interpreted this relationship causally: by minimizing the reliance on substrate-level phosphorylation, and hence the accumulation of fatigue-related metabolites during the transition, a lower VO2 (i.e. faster ̇ V O2 kinetics) allows a higher power production to be achieved for a given magnitude of O2 deficit accumulation. Critical power represents the upper limit of the metabolic steady state, and by extension also signifies the upper limit of an  O2 deficit below which muscle fatigue, reduction in work efficiency, and the O2 deficit itself will stabilize. All else being equal, therefore, faster ̇ VO2 kinetics will result in a higher CP. However, despite the strong rationale and crosssectional evidence supporting a mechanistic link between VO2 and CP, until recently, this hypothesis had not received direct experimental scrutiny.

In the first of a series of studies examining the purported determining effect of VO2 on CP, Goulding et al. [114] examined the influence of prior heavy (“priming”) exercise on pulmonary ̇ VO2 kinetics and CP during supine and upright cycling. A prior bout of priming exercise does not speed ̇ VO2 kinetics (i.e. reduce VO2) during upright cycle exercise in young healthy individuals. However, during exercise in the supine position, muscle perfusion pressure is impaired and VO2 becomes O2 delivery dependent [114–120]. Hence, in a young healthy population, prior heavy exercise (which enhances muscle O2 delivery, [115, 121, 122]) would be expected to reduce VO2 during supine but not upright cycling. Accordingly, should VO2 exert a determining effect on CP, an increase in CP during supine, but not upright, the exercise would be observed following priming exercise as compared with control conditions. It was demonstrated that when priming exercise was conducted in the supine position, VO2 was indeed reduced and CP concomitantly increased, whereas during upright exercise, both VO2 and CP were unaffected [114]. These findings therefore provided the first experimental evidence that VO2 is mechanistically related to CP.

Because of the nature of the priming intervention utilized in this first study [114], however, it was not possible to separate any independent effect of a reduced VO2 (i.e. slowed ̇ V O2 kinetics) on CP from that of an improved O2 availability as a consequence of the priming exercise. Indeed, the strong correlation observed between VO2 and CP for upright exercise was absent for supine exercise [114]. Hence, it remained plausible that, at least in supine exercise, other physiological factors, such as muscle O2 availability, and its distribution relative to ̇ VO2, determine CP, with the concomitant improvements in VO2 and CP being an artifact of shared physiological determinants, without any dependence of  CP on VO2 per se. Hence, confirmation or refutation of the hypothesis that VO2 is an independent determinant of CP required an intervention that could alter VO2 without any concomitant alterations in muscle O2 delivery, such that the independent effect of VO2 on CP could be observed. When exercise is initiated from an elevated baseline work rate, VO2  is greater than when compared with work initiated from a baseline of unloaded cycling [123–126]. Importantly, this slowing of the ̇ VO2 kinetics appears to occur independently of any alterations in O2 availability [127–129].

Hence, we conducted two further studies that assessed the influence of exercise initiated from an elevated baseline work rate on VO2 and CP in the upright [130] and supine  [117] positions. In both of these studies, VO2 was greater  (i.e. VO2 kinetics was slower) and CP was correspondingly reduced during work-to-work exercise compared with when exercise was initiated from a baseline of unloaded cycling  [117, 130]. Crucially, indicators of O2 availability determined via NIRS were either improved [130] or unchanged [117] during work initiated from an elevated baseline, suggesting that the slowing of ̇VO2p kinetics brought about by this intervention was wholly independent of changes in microvascular O2 availability. Taken together, these findings therefore demonstrate an independent effect of VO2 on CP [130], and that this effect persisted even in situations where O2 delivery is substantially impaired [117].

The determining effect of VO2 on CP observed in healthy populations [64, 114, 117, 130] was later confirmed in a study that assessed the impact of priming exercise on ̇ VO2  kinetics and CP in a population of individuals with type 1 diabetes mellitus [131]. In this population, priming exercise speeded ̇ VO2 kinetics and increased CP during subsequent severe-intensity cycle exercise. Notably, these effects were accompanied by a concomitant speeding of muscle deoxygenation kinetics determined via NIRS [131]. As the muscle deoxygenation signal derived via NIRS represents the relative balance between O2 delivery and utilization within the interrogated region, a relative speeding of muscle deoxygenation kinetics suggests that the effects of priming exercise on VO2 were predominantly due to an upregulation of otherwise impaired intracellular mechanisms of mitochondrial O2 utilization, rather than O2 delivery [131]. Taken together, therefore, substantial recent evidence has accumulated to demonstrate that rates of intracellular O2 utilization at the onset of exercise, encapsulated by VO2, can influence CP independently of factors related to mitochondrial O2 provision.

3 Interaction of Factors Determining CP

The studies of Goulding et al. [8, 64, 65, 114, 117, 130, 131] provide convincing evidence that VO2 is an independent determinant of CP. As reviewed above, there is also evidence for an independent determining role of convective and diffusive O2 delivery in influencing CP. That each of VO2, convective, and diffusive O2 delivery has an independent role in determining CP is evinced by the fact that each can alter CP without a concomitant change in the other.

The proportion of CP explained by VO2 has been reported to be as high as 90% in a homogenous participant group where relative exercise intensity was precisely controlled (i.e., a tolerable duration of 6 min across subjects) [14]. Our data have demonstrated R2  values of 0.64–0.90 for the relationship between CP and VO2 during upright exercise  [60, 111, 127, 128]. Collation of these data across differing exercise intensity domains and populations, including hyperoxia conditions, yields an R2=0.60 (Fig. 3A; data from [131] previously unpublished), with a slope of~0.03 W kg−1 s −1. However, this includes data from diseased populations (type 1 diabetes [131]) and hyperoxia [65], both of which might be expected to confound the analysis as the latter may distort the relationship between pulmonary and muscle VO2  and the former has a slope (0.01 W kg−1 s−1) significantly different to the healthy populations. The exclusion of diseased and hyperoxic data blunts the strength of the relationship between CP and VO2 (R2=0.43; Fig. 3B). However, the strength of this relationship increases markedly when only moderate-intensity exercise in healthy participants is considered (R2=0.79; Fig. 3C). The slope of the relationship between VO2 and CP was preserved across this latter analysis, and taken together, CP appears to be well predicted from VO2 when the latter is precisely determined for a given relative exercise intensity, varying by~0.03 W kg−1 per second change in  VO2. However, and perhaps exemplified by the data from type 1 diabetes [131] and hyperoxia [65], when this relationship is expanded to cover the range of values for VO2 encountered across the animal kingdom (Fig. 3D), the relationship with CP appears curvilinear, but preserved, suggesting a fundamental linkage of CP with muscular bioenergetics across species. Moreover, when the human-only data are considered and the speed of oxygen uptake kinetics expressed as a rate constant (i.e., 1/VO2), the relationship with CP is linear (Fig. 3E). Accordingly, when the scope of human aerobic fitness is considered, the relationship between CP and VO2 can be considered to be hyperbolic, with previously published linear relationships [14, 104] being an artifact of participant homogeneity. By contrast, only one previous study has titrated the effect of oxygen delivery on CP [63]. Here, the reduction in CP with increasing altitude as a proxy for oxygen delivery was established, simulated by changes to FiO2. A non-linear (third-order polynomial) relationship was established with increases in altitude producing progressively larger reductions in CP. Critical power was reduced by 74 W with a 4000-m increase in altitude, though any such relationship will inevitably be impacted by the effect of reductions in FiO2 increasing VO2 (i.e. slowing ̇ VO2 kinetics).

Given the evidence reviewed herein, we, therefore, propose that each mitochondrial O2 utilization (encapsulated by the VO2 parameter), convective and diffusive O2 delivery exert independent effects on CP such that intracellular O2 utilization and O2 transport interact to determine CP (Fig. 4). Exceptions to this include where pulmonary limitations (e.g. [34]) are dominant factors in limiting exercise tolerance to the extent that they dictate the shape of the power–duration relationship.

The precise mechanisms underpinning such an interaction have not been fully elucidated; however, a starting point is to consider the inexorable loss of intracellular homeostasis, and thus unsustainable rise in O2 deficit, during exercise above, but not below, CP. This is accompanied by a mirror-like association between peripheral fatigue [107, 132] and the loss of exercise efficiency [109, 133, 134] that occurs during exercise above CP [135]. Of the factors that accumulate as a result of the O2 deficit, [Pi] is a prime candidate for the common denominator between fatigue and efficiency owing to its central role in muscle fatigue and task failure [136]. A recent in silico study by Korzeniewski and Rossiter [10] tested the hypothesis that accumulation of [Pi] during the transition from rest to work could explain both the loss of intracellular homeostasis during supra-CP exercise and the fatigue-related termination of exercise. Using a validated model of the human bioenergetic system, Korzeniewski and Rossiter [10] defined a “critical” (i.e. threshold) [Pi] above which further [Pi] accumulation drove an increase in the requirements for ATP turnover (i.e. an increased ATP cost of muscle contraction) and a “peak” (i.e. limiting) [Pi] at which exercise would cease. The additional ATP turnover driven by [Pi] accumulation resulted in a self-propagating positive feedback loop where additional ATP turnover resulted in increased [Pi], which caused fatigue and additional ATP   turnover until the pre-defined peak [Pi] (and accompanying muscle ̇ VO2max) was achieved. By contrast, when [Pi] accumulated below or only marginally above critical [Pi], this positive feedback loop stabilized such that [Pi] did not attain peak values and muscle oxygen uptake attained a steady state. Based on these findings, we therefore recently proposed a model whereby muscle O2 consumption kinetics determine CP by dictating the magnitude of O2 deficit (and thus [Pi], amongst other factors) accumulated during a given exercise transition [8]. Slow ̇ VO2 kinetics begets large intracellular perturbations whereas fast ̇ VO2 kinetics engenders smaller intracellular perturbations for a given metabolic rate at exercise onset [102, 104, 110, 137]. Accordingly, more rapid ̇ VO2 kinetics will enable a higher exercise intensity before a critical value of [Pi] is breached, thereby increasing critical power, all else being equal. Importantly, simulating alterations in PO2im within the computer model of Korzeniewski and Rossiter [10] resulted in the changes in VO2 and CP predicted by the evidence reviewed in each of the previous sections [10].

Alongside other O2 deficit-related factors, that breaching a critical [Pi] results in an inexorable cascade of increasing  [Pi], fatigue, and ATP turnover is also consistent with the evidence reviewed herein whereby convective and diffusive O2 delivery has a determining effect on CP. O2 delivery is known to regulate the concentrations of phosphate metabolites at a given metabolic rate, such that when intracellular PO2 is higher, the intracellular perturbations incurred for [Pi], [PCr], and [ADP] are reduced, whereas the reverse is true when intracellular PO2 is lower [49, 50, 54, 138]. From these observations, it follows that the aforementioned effects of convective and diffusive O2 delivery and intracellular O2 utilization on CP stem from their impact upon the intracellular metabolic state, or more specifically, the rate of ATP turnover at which a critical threshold for [Pi] (which is itself a proxy for a collection of intracellular metabolites reflecting the intracellular state of fatigue) is attained. Hence, faster  ̇ VO2 kinetics, as well as increased O2 delivery, exert their effects on CP by reducing the intracellular metabolic perturbations required to sustain a given rate of ATP turnover, thus enabling a higher power output to be achieved before CP is reached.

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