A Masterclass On VO2max And The Limits Of Human Performance
In this article you'll learn about the determinants of VO2max, how VO2max increases, and how you can identify physiological limitations to improve your VO2max.
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🫀Challenging Conventional Paradigms of Maximal Exercise Performance
“Exercise more than any other stress taxes the regulatory ability of the cardiovascular system. The advantage to the investigator is that more is learned about how a system operates when it is forced to perform than when it is idle.” -Loring B. Rowell
Exercise, as a research tool, allows scientists to investigate human physiology when pushed to its limits, providing us with insights that we couldn’t otherwise discover. One reason for this is that it’s exceptionally difficult to record uniform and consistent measurements of an individual’s physiology at rest. Joseph Barcroft understood this as early as 1934 when he wrote, “scaling from measurements at rest suffers from the marked random variation characterizing that loosely defined state” in Features in the Architecture of Physiological Function. Joseph Barcroft’s key point was that the term rest is too seemingly arbitrary to be useful. For example, am I resting as I sit upright in a chair? Or, am I only resting if I lay supine without moving a single muscle? These questions may seem pedantic, but they have real consequences in research where conditions need to be standardized to the utmost degree.
Rather than grappling with the aforementioned issues physiologists have adopted a different method of collecting uniform measurements. It’s long been known that the most uniform and consistent measurements of human physiology occur at an individuals’ maximal exercise capacity. The most common test used to interrogate an exerciser’s maximal work capacity is the ramp incremental VO2max test, which is a measurement of the entire cardiovascular system’s functional capacity. You can think of an exerciser’s VO2max as the maximum integrated capacity of their pulmonary, cardiovascular, and muscular system to uptake, transport, and utilize oxygen respectively.
Despite VO2 being a relatively simple measurement of total body oxygen consumption there is a bit of nuance as to how a true VO2max is attained. For example, attaining a true maximum VO2 measurement requires that a certain fraction of an exerciser’s total muscle mass is engaged during activity. As a result, the term VO2max only applies to the highest attainable VO2 value an individual can reach, independent of exercise modality. On the other hand, the term VO2peak is contextual and refers to the highest VO2 value achieved during a given exercise bout. If you were to exercise a small fraction of total muscle mass by using an arm ergometer your VO2peak would be much lower than your VO2max. However, if you were to perform a full body exercise, like rowing, your VO2peak would be equal to your VO2max. Interestingly, you do not need to exercise your full body to reach a true VO2max. You only need to cross a critical mass of engaged skeletal muscle and past that point engaging even more muscle will not lead to greater whole body oxygen consumption.
🫀Determinants of Maximal Oxygen Consumption
The idea that there is a finite rate that oxygen can be transported from the environment to the mitochondria of exercising muscles began in the early 1920’s with the Nobel prize laureate Archibald Hill’s work. Since then VO2max has become one of the most ubiquitous measurements in exercise science.
VO2max is calculated with the Fick equation, which states that the volume of oxygen consumed at any given time is the product of an exerciser’s cardiac output (which is itself the product of heart rate and stroke volume) and the difference in oxygen concentration between their venous and arterial blood, also known as the arteriovenous difference. Using the Fick equation one can derive that there are two ways that an individual can increase their VO2max. The first is increasing oxygen supply and the second is by increasing oxygen utilization. However, the traditional viewpoint is that interindividual differences in VO2max are almost entirely due to differences in stroke volume and cardiac output between exerciser’s. The idea is exemplified in Lundby, Montero, and Joyner’s paper titled Biology of VO2max: looking under the physiology lamp where they state, “The dominant and deterministic physiological pathways that account for a vast majority of inter-individual variability in VO2max are well known and center on total body hemoglobin content and peak cardiac stroke volume and as a result cardiac output.”
It makes sense that an exerciser’s stroke volume would play a large role in determining their VO2max when you consider the fact that an enlargement of the heart’s ventricles, enhanced cardiac contractility, and increases in blood volume are all common adaptations from endurance training. These adaptations all allow for an increased filling of the ventricles between heart beats, and in turn they increase stroke volume. Additionally, it's well known that endurance training increases hemoglobin concentrations in blood, which can increase stroke and VO2max. Per-Olof Åstrand was the first to demonstrate this relationship when he showed that the differences in VO2max values between adults and children, and between adult men and adult women, are primarily due to differences in hemoglobin concentrations. Since then it has been shown that acute reductions in hemoglobin concentrations result in decreased endurance performance and oxygen carrying capacity in the blood, even when blood volume is maintained. Conversely, increases in hemoglobin concentration and blood volume are associated with enhanced endurance performance. The reason is that increases in blood volume cause end-diastolic volume, ejection fraction, and stroke volume to go up, which are all associated with increased VO2max values.
Collectively, the aforementioned factors provide evidence for the existence of a cardiovascular oxygen supply limitation. However, this evidence does not mean that VO2max cannot be limited by other factors such as oxygen utilization in the working muscles, or pulmonary oxygen supply. In other words, the existence of one phenomenon does not disprove another. For example, elite endurance athletes with very high maximal cardiac outputs will often present with pulmonary diffusion limitations because of the red blood cells moving through the pulmonary capillaries so quickly that they cannot adequately pick up oxygen. This form of pulmonary diffusion limitation was first observed in Peter Snell, the former world record holder for the fastest mile run. Peter Snell performed a maximal effort step test on a treadmill, and finished with an peripheral oxygen saturation of 80%, systemic oxygenation. Additionally, this finding was later confirmed by Jerome Dempsey, Scott Powers, and colleagues, when they showed that arterial deoxygenation occurs in some high trained endurance athletes and that when these subjects breath in hyperoxic gas mixtures their hemoglobin saturation and VO2max increase. It’s also common for elite Crossfit competitors to experience significant decreases in peripheral oxygen saturation after competition intensity work bouts. This suggests that pulmonary gas exchange can limit total body oxygen consumption in highly trained athletes who exhibit exercise-induced reductions in peripheral oxygenation at sea level. It also suggests that a healthy pulmonary system can become a so-called limiting factor to oxygen transport and utilization as well as carbon dioxide transport and elimination during maximal effort exercise in the highly trained.
According to the Fick equation, an increase in VO2max must be accompanied by a concomitant improvement in maximal cardiac output or a widening of the arteriovenous oxygen concentration difference. Knowing this, it’s clear why a pulmonary diffusion limitation would decrease VO2max and impair performance. If an exerciser’s peripheral oxygen saturation decreased, it would minimize the concentration difference between their arterial blood, which should be highly oxygenated, and their venous blood, which has a lower oxygen concentration. In these cases improving pulmonary function would widen the arteriovenous concentration difference, thus increasing VO2max. However, oxygen utilization limitations may also be present, which would truncate the arteriovenous concentration difference by increasing the oxygen content of venous blood. In these cases improving an exerciser’s oxygen extraction and utilization would widen the arteriovenous difference, increasing VO2max as a consequence.
🫀Redefining VO2max: An Integrated Perspective
Traditionally VO2max has been defined as the maximal rate of oxygen consumption measured during intense exercise, and it’s long been believed that stroke volume is the dominant and deterministic limiter of VO2max. However, there are well-established cases where VO2max is limited by other physiologic factors. As a result, It’s more appropriate to define VO2max as the maximum integrated capacity of the pulmonary, cardiovascular, and muscular systems to uptake, transport, and utilize oxygen, respectively.
It’s now clear that VO2max can be limited by a range of physiological factors such as an exerciser’s pulmonary diffusion capacity, maximal cardiac output, peripheral circulation, and the oxidative capacity of skeletal muscle. However, most coaches and physiologists still do not hold this view. Instead, they believe that the cardiovascular system’s capacity to transport oxygen to the working muscles is the principal determinant of VO2max. This idea emerged as a result of Archibald Hill’s research in the early 1900’s.
While Archibald Hill’s work undoubtedly contained many partial truths, its partial validity shouldn’t mask its clear shortcomings. It is crucially important to realize that Archibald Hill formulated his hypotheses based on a small number of measurements of expired respiratory gasses. He did not include any measurements of cardiovascular function, pulmonary function, or any measurements of skeletal muscle contractile and metabolic function. An unfortunate consequence is that generations of exercise physiologists have been taught that respiratory gas analysis, in the absence of other biomarker measurements, can give you answers about the factors that limit human performance. I believe this is false. For example, in Archibald Hill’s quantitative estimates he calculated that arterial blood would be 90% saturated during all-out exercise and that mixed venous blood would be 10-30% saturated. He also assumed that these values would generalize to all exercising individuals. If this were true, and the arteriovenous concentration difference were fixed, it would lead to the natural conclusion that cardiac output is the primary determinant of VO2max, as Hill and generations of physiologists after him asserted. However, we know these values are not only not fixed, but vary considerably between exercising individuals. Thus, opening the door for a more nuanced understanding of the limiting factors for maximal exercise performance.
The fact that VO2max can in fact have different rate-limiting factors opens the door to a new training paradigm in which individuals can identify physiological limitations and train in a targeted fashion to improve them, which is the topic of a previous series including the following article:
🫀How Does VO2max Increase?
The cardiovascular system has a profound ability to adapt and change when it is repeatedly exposed to exercise-induced stressors. Physical conditioning, from exercise, increases the functional capacity of the cardiovascular system in two distinct ways. First, physical conditioning increases maximal cardiac output by increasing heart rate and/or stroke volume. Second, conditioning can lead to adaptations that widen the arteriovenous oxygen concentration difference during exercise which is accomplished by increasing arterial oxygen saturation or increasing fractional oxygen extraction.
In healthy young adults who are previously untrained VO2max can increase by upwards of 20% after three months of training. Approximately half of the increase in VO2max can be attributed to increases in maximal cardiac output and oxygen extraction respectively. Additionally, the exercise induced increases in cardiac output are due almost entirely to increases in stroke volume, and not heart rate. However, in advanced athletes who have undergone years of training 30% of improvements in VO2max are attributed to increases in stroke volume, 10% are attributed to increases in maximal oxygen extraction, and the remaining 60% of improvements are attributed to enhanced movement economy and pulmonary diffusion.
Based on the broad body of exercise physiology literature it’s apparent that the peripheral adaptations that lead to increased oxygen extraction occur rapidly in response to exercise. For example, improvements in oxygen extraction and muscle oxygen utilization have been observed in as little as two to three weeks of dedicated training. Cardiovascular and circulatory adjustments, on the other hand, occur over much longer time scales. The rates of adaptation in different bodily systems helps explain why oxygen extraction limitations are less common among elite athletes.
🫀Increasing Stroke Volume
There are three proposed mechanisms contributing to exercise-induced increases in stroke volume. These include changes in the myocardial contractile state, changes in ventricular after-load, and changes in ventricular preload.
Although it has traditionally been believed that changes in the myocardial contractile state lead to exercise-induced increases in stroke volume that theory can be quickly dispensed with. While it is true that the myocardial contractile state increases as exercise intensity increases, additional enhancements to the myocardial contractile state over time with training are small because left ventricular ejection fraction is already high at 85%. Additionally, end-systolic volume is low at peak exercise. As a result, it’s unlikely for exercise to yield further improvements in the myocardial contractile state.
Ventricular afterload is the amount of pressure that the heart must work against to eject blood during systole, which is the phase of the heartbeat when the heart muscle contracts and pumps blood into the arteries. While it has been proposed that changes in afterload account for some of the observed increases in stroke volume with physical conditioning I find this to be implausible. There is little evidence demonstrating significant effects of training on ventricular afterload. Additionally, cross sectional studies show that highly trained athletes and sedentary individuals have similar mean arterial pressure at their respective maximal cardiac outputs. This suggests that physical training is accompanied by peripheral adjustments that match total vascular conductance to maximal cardiac output, without significant changes to ventricular after-load.
Collectively the aforementioned information suggests that the bulk of increases in stroke volume as a product of physical conditioning are attributed to changes in ventricular preload. Ventricular preload, also known as end-diastolic volume, is the amount of stretch that the cardiac muscle cells experience at the end of ventricular filling between heart beats. Based on cross sectional studies, it’s been shown that ventricular preload is significantly elevated at rest and during exercise in athletes as compared to sedentary individuals. It is also believed that structural changes in the heart allow for increased ventricular preload, which is supported by medical imaging and autopsy studies showing that chronic physical training increases ventricular volume and ventricular wall thickness and that there is a significant correlation between heart size, stroke volume, cardiac output, and VO2max. Additionally, long term-training results in meaningful increases in blood volume, which can have a small but noticeable positive impact on ventricular preload.
🫀Arterial Oxygen Saturation During Exercise
It’s important to remember that the circulatory system is a closed loop where oxygen travels from the heart to the working muscle and back along the following route: heart → artery → arteriole → capillary → venule → vein → heart. When we record arterial oxygen saturation, often referred to as SpO2 or SaO2, we are measuring at the location of the artery. Arterial oxygen saturation depends both on hemoglobin concentration as well as its oxygen binding capacity, pulmonary diffusion capacity, and alveolar ventilation.
It’s commonly assumed that both arterial oxygen content and hemoglobin saturation are well maintained during exercise. However, during maximal effort exercise arterial hemoglobin concentration and oxygen carrying capacity can both rise by up to 10%. This occurs when plasma water is lost into the active muscle cells and interstitial fluid as the concentration of osmotically active particles in the muscles rise.
Insofar as an individual’s arterial oxygen capacity rises, while their oxygen content remains constant, their arterial oxygen saturation will fall. This is why you’ll often see a meaningful decrease in peripheral oxygen saturation during very high intensity exercise. Additionally, the aforementioned decrease in peripheral oxygen saturation during high intensity exercise is partly attributable to reductions in arterial pH and a rise in temperature, both of which lower arterial oxygen saturation at a given oxygen binding capacity. In very extreme cases you may see peripheral oxygen saturation fall below 90%, though this is much more common in elite endurance athletes. In these cases the extreme drops in peripheral oxygen saturation are caused by a pulmonary diffusion limitation.
🫀Skeletal Muscle Oxygen Extraction During Exercise
The Fick equation states that the volume of oxygen consumed at any given time is the product of an exerciser’s cardiac output and the difference in oxygen concentration between their venous and arterial blood. Muscle oxygenation is measured in the microvascular capillaries, which approximates mixed venous oxygen content. The two populations where the lowest muscle oxygenation values are observed are high training athletes with enhanced oxygen extraction capabilities, and heart failure patients who have very low cardiac output due to an insufficiency of the heart as a pump.
Highly trained athlete’s enhanced oxygen extraction capabilities are explained by a range of factors. Unlike cardiac muscle where moist capillaries are open at all times, only a small fraction of capillaries are perfused in skeletal muscle during rest. As a result, the diffusion distance between capillaries and muscle fibers is large. When you consider these large diffusion distances and the fact that the mean transit time of red blood cells through the muscle capillaries are very short, there is little time for oxygen extraction and uptake by the skeletal muscle at rest. However, during exercise the number of open capillaries increases, which reduces the diffusion distance and increases capillary blood volume significantly. As a result, the mean transit time of red blood cells increases, which allows for more oxygen to be unloaded from the blood to the working muscle. As a consequence of increased capillary recruitment during exercise, each muscle fiber is supplied by more capillaries than at rest. Therefore, to maintain high oxygen extraction across the muscle there needs to be a balance between optimal rates of muscle blood flow, capillary blood volume, and the minimum mean transit time of red blood cells to release oxygen for skeletal muscle uptake. This balance is well preserved during intensity exercise where both muscle blood flow and oxygen extraction increase significantly, thus increasing whole body VO2 as well. In these cases capillary blood volume and red blood cell mean transit time are large enough to allow oxygen to be released from hemoglobin and diffuse all the way from the capillaries to the mitochondria of muscle cells.
Oftentimes exercises with low training ages will present with oxygen extraction limitations as a result of low mitochondrial and capillary density. Additionally, there are instances where athletes with very high maximal cardiac outputs will present with oxygen extraction limitations as well, particularly when they eschew high intensity training for extended time periods. In both cases increasing muscle mitochondrial and capillary density, and improving vascular conductance, will lead to enhanced skeletal muscle oxygen extraction.
🫀Mitochondrial DNA, Maximal Oxygen Consumption, and Metabolic Efficiency
For decades mitochondria have been seen as nothing more than microscopic cellular powerhouses. However, mitochondria also play critical roles in regulating cell death and survival, aging, and various physical adaptations to endurance training. It’s well known that mitochondria are the only organelles in animal cells with their own discrete genome, which is attributed to their endosymbiotic origin. Thus, while we inherit our chromosomal DNA from both our parents, our inherited mitochondrial DNA comes exclusively from our mothers. This maternal inheritance of mitochondrial DNA, combined with the high mutation rate of mitochondrial DNA, allows us to track our maternal lineage back through generations. You can envision these mitochondrial DNA lineages as a giant tree, where the clustered groups on the different branches make up different haplogroups. These haplogroups arose in geographically localized populations, and their distribution across the world has allowed researchers to reconstruct the ancient migrations of women across the globe.
It is well accepted that one of the main determinants of the individual variation in endurance performance is the metabolic properties of skeletal muscle, particularly its mitochondrial oxidative potential, which is coded by mitochondrial DNA passed down through the maternal lineage. This material DNA codes for some of the most essential polypeptides of the mitochondrial energy generating system, most notably OXPHOS, which generates cellular energy by the oxidation of dietary calories. As electrons move down the electron transport chain the energy released pumps protons out across the inner mitochondrial membrane to generate a proton electrochemical gradient, which the ATP synthase enzyme can employ to drive ATP synthesis. Therefore, the mitochondrial genome provides a few candidate genes for the study of elite endurance athletic status.
Since mitochondrial DNA genes have a central role in OXPHOS expression, different haplogroups and functional variants in mitochondrial DNA can have massive impacts on human physiology and exercise performance. For example, the efficiency with which the electron transport chain generates the proton gradient and by which the proton gradient is converted into ATP is referred to as the coupling efficiency. Humans can differ substantially in their coupling efficiency due to mitochondrial DNA polymorphisms. Since a dietary calorie is a unit of heat, every calorie burned by the mitochondria generates one calorie of body heat. Tightly coupled mitochondria generate the maximum ATP and minimum heat per calorie burned and thus could be beneficial in warmer climates, while loosely coupled mitochondria must burn more calories for the same amount of ATP, generating more heat, and could be of benefit in colder climates. The importance of heat generation per unit of energy created will be discussed shortly.
As previously mentioned, aerobic ATP generation by OXPHOS is a vital metabolic process for endurance exercise. Notably, mitochondrial DNA codifies 13 of the 83 polypeptides implied in the respiratory chain. As such, there is a strong rationale for identifying an association between mitochondrial DNA variants and endurance phenotypes.In the context of endurance performance, high sustained ATP synthesis is a huge competitive adone of the most important competitive advantages. It is increasingly recognized that there is a conserved evolutionary trade-off between maximum-power output using fermentative pathways and maximum metabolic efficiency using complete oxidative phosphorylation, which is rooted in differences in the catalytic capacity of the different pathways. The phenomenon is known as overflow metabolism. The reason that metabolic overflow occurs stems from a bottleneck deep inside the mitochondria termed complex-I. At lower power outputs such as during long slow distance training, the muscles energy stores are burned efficiently using complex-I. When power output is increased, complex-I reaches its full capacity, so to be able to match the energy requirements mitochondria start to bypass complex-I choosing a metabolic strategy with a higher capacity but a lower efficiency. This allows the muscles to produce more power, but also more heat. Going into power mode thereby means that your energy stores are zapped faster and the athlete risks hitting the wall before reaching the finish line.
This becomes relevant when we think of rate limiting factors for increasing an individual’s VO2max. While many athletes use VO2max as a measuring stick for performance improvement, they seldom consider that improving VO2max may come at the cost of decreased efficiency. For example, Oskar Svendson has been recorded as having the highest VO2max of all time. Naturally, this leads to the question of why wasn’t he a faster cyclist? Mikael Flockhart and Filip Larsen offered a suggestion to this question in their 2019 paper in the Journal of Applied Physiology titled, Physiological adaptation of aerobic efficiency: when less is more . In essence, they suggest that Svendson has a massive engine but poor fuel efficiency and that this is no coincidence. Michael Joyner has made a similar suggestion in a paper titled, Modeling: optimal marathon performance on the basis of physiological factors , where he stated, "It may be that high VO2max values are incompatible with excellent running economy."
Interestingly, in the early 1990’s Michael Joyner had posited that the first runner to run a sub 2-hour marathon would have a high but realistic VO2max, running economy, and lactate threshold without any of these individual variables being off the charts. He was clear that the individual with the highest VO2max value would be an unlikely candidate. The reason for this is that it’s physiologically implausible for someone with a very high VO2max to have a world-class running economy in the same way that it’s unlikely to hit the mega millions jackpot twice. Interestingly, Eliud Kippchogee perfectly fits this bill. He has a high VO2max at 78 ml/kg/minute, but it is by no means off the charts. However, his economy sets him apart, which allows him to use 0.2 ml/kg/minute of oxygen per minute than his competitors at a top speed. He has struck the perfect balance between power and efficiency.
Research suggests that between two elite runners with equal race times, the individual with the higher VO2max will have a lower economy and vice versa. This surely applies to Oskar Svendson and is a topic of discussion in Bent Ronnestad and colleagues' paper titled, Case Studies in Physiology: Temporal changes in determinants of aerobic performance in an individual going from alpine skier to world junior champion time trial cyclist .
Interestingly, Oskar Svendon’s data suggests that his gross efficiency (the power delivered to the bike pedals divided by the rate he burned calories) was highest before he began science training and as his VO2max progressively increased, his efficiency dropped at a disproportionate rate. A potential mechanism for this lies in Avlant Nilson and colleagues' paper titled, Complex-I is bypassed during high intensity exercise , which hammers home the aforementioned concept that at very high intensities mitochondria bypass complex-I and rely on metabolic strategies that allow for higher capacity, but with lower efficiency. This strategy will enable muscles to produce more power, but also more heat. It stands to reason that the individuals with the highest VO2max values in the world, also have some of the most loosely coupled mitochondria and vice versa. Remember, loosely coupled mitochondria are beneficial in colder climates, whereas highly coupled mitochondria benefit in warmer climates.
Interestingly, some of the highest VO2max values have been recorded by athletes of northern European descent, whereas individuals living closer to the equator tend to have lower than average VO2max values when adjusted for age and body mass. While investigators have begun to identify mitochondrial haplotypes associated with both of these adaptations, more research is needed before consumer DNA tests can be used for talent identification.