Both authors contributed to the conception and design of the work, acquisition, analysis, and interpretation of data, drafting of the work and revising it critically for important intellectual content. Both authors have read and approved the final version of this manuscript and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
Correspondence: Michael J. Joyner, Department of Anesthesiology & Perioperative Medicine, Mayo Clinic, Rochester, MN 55905, USA. ude.oyam@leahcim.renyoj
The publisher's final edited version of this article is available free at Exp PhysiolIn this paper we review the physiological determinants of V ˙ O 2 max and discuss the role this variable plays as a determinant of endurance exercise performance. Because the ability to sustain a given pace during a competitive athletic event requires competitors to ‘manage’ fatigue and go as fast as possible without fatiguing prematurely, V ˙ O 2 max is one of the variables that sets the physiological upper limit for sustained energy production by the contracting skeletal muscles.
Keywords: cardiac ouput, haemoglobin, stroke volumeThis paper is based on a symposium presentation given at Physiology 2019 in Aberdeen, Scotland. The focus of the symposium was ‘Fatigue as a limitation to performance’. In this context, to discuss fatigue as a limitation to performance it is perhaps useful to define limitations to performance. It is also important to define what kind of performance because the limiting factors in a strength or sprint task differ from those in a longer duration ‘endurance’ task. As the duration of a task or human athletic event becomes longer, the predominate energy source becomes progressively ‘aerobic’ meaning that a larger and larger fraction of the ATP needed to fuel skeletal muscle contractions comes from the oxidation of glucose and fatty acids by the mitochondria (Costill, 1970). Because disruption of intramuscular homeostasis by one of several mechanisms can contribute to skeletal muscle fatigue, this also means that this ATP generation can occur in a manner that typically is ‘less disruptive’ to homeostasis.
With these concepts serving as a framework, we will first define what is meant by V ˙ O 2 max and discuss how it fits into the bigger picture of endurance performance. We will then focus on the physiology underpinning V ˙ O 2 max and comment on what research tells us about the genetics of V ˙ O 2 max .
During endurance exercise such as running or cycling, as the speed or power output (i.e. exercise intensity) increases, there is an increase in whole body oxygen consumption ( V ˙ O 2 ) driven primarily by increased oxygen demand and consumption in the contracting skeletal muscles. The increased oxygen demand and consumption is accompanied by the well-known increases in heart rate and minute ventilation. As exercise intensity approaches maximal levels, there is a levelling off of oxygen consumption with no further increase seen with greater exercise intensities. Figure 1 is an individual example of the levelling off in a fit young subject. During routine testing of many humans, a ‘levelling off’ of V ˙ O 2 is not readily observed, and therefore criteria such as a very high respiratory exchange ratio and a peak heart rate near predicted maximal levels are often used to evaluate whether a test is truly ‘maximal’.
Increases in V ˙ O 2 , V ˙ CO 2 and heart rate (HR) during an incremental exercise test on a cycle ergometer in a well-trained young male subject who was an experienced by not elite cyclist. This figure shows the progressive increase and levelling off of V ˙ O 2 with an increasing workload up to the point of exhaustion
In general, values for V ˙ O 2 max range from 35 to 50 ml kg −1 min −1 in normally active healthy young men, with young healthy women typically about 10% lower. The lower V ˙ O 2 max values in healthy women are due to the general tendency for women to have more body fat and less oxygen carrying haemoglobin than men. This wide range of V ˙ O 2 max values reflects, in large part, things like body weight and the use (or lack of) of active transportation via cycling. In the USA the impression among many investigators is that V ˙ O 2 max values expressed per kg of body weight are declining in the young due to a 5–10% increase in body weight associated with the obesity pandemic.
In elite endurance athletes, V ˙ O 2 max values in the 70–85 ml kg −1 min −1 range are typical for men, with elite women again being perhaps 10% lower on average. Additionally, there have been values higher than 90 ml kg −1 min −1 reported in men and there is evidence that V ˙ O 2 max is scaled to body size (Jensen, Johansen, & Secher, 2001; Pate & O’Neill, 2007; Pollock, 1977; Ronnestad, Hansen, Stenslokken, Joyner, & Lundby, 2019).
It is hard to say for certain who made the first measurements, especially in elite athletes, of V ˙ O 2 max using something approximating modern techniques and criteria. However, in the middle 1930s Robinson and colleagues working at the Harvard Fatigue Lab measured oxygen consumption during very fast running in world record holding middle distance runners (Robinson, Edwards, & Dill, 1937). They reported a value of ~76 ml kg −1 min −1 in Don Lash, who was the then world record holder in the 2 mile (3218 m) run with a time of just less than 9 min. It is interesting to note that the training of the elite runners of that era was incredibly ‘light’ by modern standards but did include what would now be termed high intensity training. This observation anticipates the role that training intensity plays when considering how humans respond to standardized training programmes in both research studies and training for athletic competitions (Bacon, Carter, Ogle, & Joyner, 2013).
A second caveat comes from the classic Dallas bedrest study conducted in the middle 1960s as part of an effort to begin to understand what weightless environments associated with prolonged space flight might do to physiological function (Saltin et al., 1968). In this study, five college-age men (two athletes) volunteered for 3 weeks of bedrest. All five men showed marked declines in V ˙ O 2 max . These declines during bedrest were associated with reductions in maximal stroke volume and cardiac output and were reversed by retraining after the period of bedrest.
Together these two caveats emphasize the point that in selected individuals a relatively modest dose (by current standards) of very high intensity training can be associated with very high V ˙ O 2 max values. They also show that complete detraining for only a few weeks can cause a precipitous decline in V ˙ O 2 max and it has been noted that the impact of 3 weeks of bedrest on exercise capacity is similar to 30 years of ageing (McGuire et al., 2001).
Using the marathon distance (42.2 km) as an example, the current concept is that a high V ˙ O 2 max is essential for a fast time, but other factors contribute as well. The exercise intensity for competitive events longer than 15–30 min is typically less than V ˙ O 2 max for most athletes, with values perhaps approaching V ˙ O 2 max during the finishing ‘kick’ of a race. For the marathon, some elite athletes can likely sustain 85% of V ˙ O 2 max or higher for several hours. This means that their so-called performance V ˙ O 2 is 85% of their maximum and typically at a pace that is at or slightly above their so-called lactate threshold (Davis, 1985; Farrell, Wilmore, Coyle, Billing, & Costill, 1979) – the lactate threshold being the running speed or power output associated with a rise in blood lactate above resting values.
The other key element for performance is the efficiency or ‘running economy’ (a term used because calculations of mechanical efficiency during running are difficult) of the individual. The simple question is how much speed can an individual generate at their performance V ˙ O 2 ? For example, a more efficient or economical runner will be able to run faster at a given performance V ˙ O 2 than a less efficient of economical competitor. Historically, two great marathoners, Frank Shorter and Derek Clayton, had ‘low’ V ˙ O 2 max values (~70 ml kg −1 min −1 ) for elite runners but superb running economy (Pollock, 1977). Additionally, the recent dominance of East African distance runners has been attributed in part to their generally excellent running economy (Larsen & Sheel, 2015; Saltin et al., 1995). An important point is that when a wide range of marathon performances (2–5 h for example) are considered, the relationship between V ˙ O 2 max and finishing time is likely to be very robust. By contrast, when the finishing time range is restricted to the fastest times (e.g. less than 2:20 for men or 2:35 for women), V ˙ O 2 max alone loses its power to predict finishing time.
Oxygen consumption is defined by the Fick equation: V ˙ O 2 = cardiac output × arterial − venous O 2 difference. This can be modified to include ‘max’ in the terms of the equation and provide a template for discussing the physiological determinants of V ˙ O 2 max . In this context, the primary physiological determinant of V ˙ O 2 max in most humans under most circumstances is cardiac output. Indeed there is a tight (r > 0.9) linear correlation between peak cardiac output and V ˙ O 2 max (expressed in l min −1 ) across a wide range of values. Because maximum heart rate is reasonably similar across most young humans, stroke volume (the amount of blood pumped per heart beat) is perhaps the most critical physiological or structural component of V ˙ O 2 max in humans (Lundby, Montero, & Joyner, 2017). The high stroke volumes seen in elite athletes are due to structural hypertrophy of their heart chambers in response to training, increases in total blood volume, and high levels of venous return generated by the muscle and respiratory pump. During exercise, about 6 litres of cardiac output is required to deliver the oxygen needed to support 1 litre of oxygen consumption. This means that cardiac output values in excess of 40 l min −1 can be seen in large males who participate in sports like rowing where V ˙ O 2 max can exceed 6.5 l min −1 .
In addition to cardiac output, red blood cell mass (or total body haemoglobin) is an important co-determinant of V ˙ O 2 max (Astrand, 1952). Because red cells together with haemoglobin carry oxygen, these factors operate in concert to generate a high arterial O2 content that can deliver oxygen to the contracting skeletal muscles. In this context, a major finding of the last 30–40 years is that blood flow to contracting skeletal muscle can be very high in humans (Ekblom & Hermansen 1968; Joyner & Casey, 2015). This is especially true in highly aerobically trained elite athletes. While extraction (arterial – venous O2 difference) increases with exercise from about 25% of the oxygen leaving the heart at rest to 75% during heavy exercise, peak extraction values are generally similar across a wide range of V ˙ O 2 max values in both trained and untrained subjects. Arterial oxygen content is also maintained near resting levels in all but some elite aerobic athletes (Dempsey & Wagner, 1999). In addition to absolute cardiac output, it is also important to consider the relative distribution of blood flow. Specifically, early studies demonstrated that leg blood flow decreased when arm exercise was superimposed on cycling exercise (Secher, Clausen, Klausen, Noer, & Trap-Jensen, 1977). This competitive nature between vascular beds was conclusively demonstrated with simultaneous upper and lower limb blood flow measures in highly trained skiers (Calbet et al., 2004). In addition to working locomotor muscle, the metabolic needs of the respiratory muscles also needs to be considered. Specifically, the respiratory muscles have been shown to influence blood flow distribution, which can impact performance (Harms, Wetter, St Croix, Pegelow, & Dempsey, 2000).
The effects of endurance exercise training on V ˙ O 2 max in healthy young humans is a major topic on its own, and for the purposes of this paper, two important summary points are critical. First, the vast majority of studies are of relatively short duration lasting less than 6 months. Second, many of these studies use exercise frequencies, intensities and durations consistent with public health guidelines for physical activity (e.g. 30–60 min of moderate intensity exercise per day, three or more days per week). In response to this sort of training, previously untrained individuals will see increases in V ˙ O 2 max that range from minimal to perhaps 50%. In general these increases are independent of baseline fitness (Skinner et al., 2001).
In contrast to the lack of increase in V ˙ O 2 max seen in some humans in response to short term training studies, more intense and/or prolonged training typically generates a positive response in all humans (Joyner & Lundby, 2018; Montero & Lundby, 2017). Whether this is simply a matter of shifting the range of values upward or the generation of a more uniform response is currently unknown. The so-called ‘Hickson protocol’ that includes a series of 5 min maximal intervals and fast running on alternate days over 10 weeks causes large and relatively uniform V ˙ O 2 max increases in untrained subjects (Hickson, Bomze, & Holloszy, 1977).
It is also of interest that there are case reports of completely sedentary individuals becoming world-class endurance athletes over a period of years (Wikipedia, 2019). In studies, where cardiac output or other measures of cardiac structure and function have been made, more intense and prolonged training is associated with significant increases in stroke volume and left ventricular mass (Arbab-Zadeh et al., 2014). This sort of ‘competitive athlete’ like training is also associated with increases in blood volume and red cell mass. In the case of this type of training, there is some evidence that women may be less adaptable than men (Howden et al., 2015). Nonetheless there is clearly a need for more information on sex differences related to training responses.
A hallmark of endurance exercise training, as first shown by John Hollsozy, is an increase in the mitochondrial content of the skeletal muscles that are subject to training (Holloszy, 1967). In response to prolonged and intense training, mitochondrial content can double. When observations of mitochondrial adaptations to training were first made, it was argued that they contributed to the increase in V ˙ O 2 max seen with training. However, highly trained individuals can have similar mitochondrial adaptations in their trained muscles, yet their V ˙ O 2 max values can vary by 1.5- to 2-fold (Holloszy & Coyle, 1984; Lundby & Jacobs, 2016). Additionally, in a brilliant series of studies in rats, Davies and colleagues used dietary iron deficiency to limit mitochondrial function in skeletal muscles in conjunction with blood transfusion to normalize red blood cell parameters. With that experimental paradigm, they showed that V ˙ O 2 max could be dissociated from mitochondrial function (Davies et al., 1984; Davies, Maguire, Brooks, Dallman, & Packer, 1982). By contrast, an extended run time to exhaustion was dependent on normally functioning mitochondria. These observations are consistent with the idea that the very high lactate thresholds seen in elite endurance athletes are dependent on adaptations in the trained skeletal muscles (Coyle, Coggan, Hopper, & Walters, 1988). These findings are also consistent with the performance improvements seen over the past 80–90 years that likely occurred as athletes with high V ˙ O 2 max values extended their training volumes to several hours more per day.
In the current biomedical research environment, there is great interest in the extent to which DNA sequence variation is correlated with, contributes to, or explains phenotypic variation in humans. Along these lines, when considering V ˙ O 2 max it is useful to trace the steps required for oxygen to get from the air to the working tissues. The key steps involved in O2 transport during exercise include pulmonary ventilation, diffusion across the pulmonary capillary membrane, cardiac output and red cell mass, skeletal muscle blood flow, and diffusion of O2 from the microcirculation into the muscle. Together, these steps are termed the ‘oxygen transport cascade’. The partial pressure of O2 in the inhaled air is ~150 mmHg and after mixing with residual air it encounters diffusive resistance and other diffusive effects that result in the partial pressure of O2 being very low in contracting skeletal muscle at only a few mmHg. At this time, large genome wide association studies suggest that common DNA sequence variations only explain a tiny fraction of the variation in pulmonary function. There is also little or no information on the ‘genetics’ of pulmonary diffusing capacity. Likewise no specific variants have been observed in large numbers of elite athletes that explain even a small fraction of the very high cardiac outputs (and stroke volumes) seen in these athletes (Rankinen et al., 2016). So-called ‘polygenic gene scores’ also only explain a few beats per minute of peak heart rate. Additionally, there are no genetic signatures associated with capillary density in the muscles and, as noted above, it is possible to dissociate mitochondrial content from V ˙ O 2 max . Thus while twin and family studies suggest that elements of the O2 transport cascade are ‘heritable’ in a statistical context, a DNA-based explanation clearly linked to deterministic physiological pathways is currently unidentified (Joyner, 2019; Sarzynski, Ghosh, & Bouchard, 2017).
V ˙ O 2 max is a key determinant of endurance exercise capacity, and very high values are a prerequisite for elite performances in a wide range of endurance sports. Additionally, the ability to sustain a high fraction of V ˙ O 2 max (performance V ˙ O 2 ) with minimal disruptions in homeostasis is essential in events like the marathon. Individuals who are able to generate a high performance V ˙ O 2 and move efficiently are thus poised to sustain a fast pace in competition while avoiding or delaying fatigue. While peak cardiac output, blood volume and red blood cell mass are the deterministic physiological variables for V ˙ O 2 max under almost all circumstances, the contribution of DNA variation to the range of values seen for these deterministic physiological variables and how they adapt to training is unclear.
The limits to maximal aerobic capacity.
A synthesis of data and ideas about what limits maximal aerobic capacity demonstrates the central roles of cardiac output, stroke volume and red blood cell mass in the complex physiological responses to maximal exercise. In healthy humans these factors, along with skeletal muscle blood flow, dominate systemic delivery of oxygen to the contracting muscles and set the upper limit of aerobic energy production by skeletal muscles. In elite athletes and patients with pulmonary disease the lungs can also limit oxygen uptake and delivery.
NSERC, Grant/Award Number: RGPIN-2019-04615; NIH, Grant/Award Number: HL139854-01
