Exercise
How DNA affects your running performance and training response
Dr Haran Sivapalan
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January 18, 2023
“Gentlemen, we can rebuild him. We have the technology….Better than he was before. Better, stronger, faster.”
Unlike Steve Austin, the Six Million Dollar Man, most us do not have state-of-the-art cybernetic technology or six million dollars* at our disposal when it comes to improving our running performance. Rather, in order to get fitter, faster, and better than we were before, we must rely on good old-fashioned training.
But, do we all significantly improve in response to training?
When it comes to one major component of running performance, VO2max, the answer seems to be: no, it depends on your genetics.
*About $33 million in today’s money, adjusting for inflation.
What determines running performance?
Lots of things can influence how fast we run on a particular day, from the weight of our running shoes to the amount of air pollution in the atmosphere. When it comes to physiological parameters that determine running performance - the kinds of measurable things that quantify how well our body functions under the demands of running - the scientific literature points to three key factors:
- VO2max (or maximal oxygen consumption) - a measure of how well you take oxygen from the atmosphere and deliver it to working muscles, and how well these muscles extract oxygen to generate energy for movement.
- Lactate (or anaerobic) threshold - a measure of how well our body clears lactate and recycles it for energy, which affects how quickly we fatigue. A higher lactate threshold means that you can reach a higher running speed or intensity of exercise before lactate rapidly accumulates in the bloodstream, which occurs as lactate clearance fails to keep up with lactate production.
- Running economy - which reflects how much energy you use to run.You can think of it as similar to the “miles per gallon (mpg)” measurement of a car. For a given running speed, someone with a better running economy will consume less oxygen and burn less energy, as their body moves more efficiently.
Although there is considerable overlap between these three factors, each of them have been shown to be independently important in predicting running performance. The graph below, for example, which is from a study of Portuguese and French national running teams, shows that individuals with a higher VO2max had faster marathon times. The same study found that differences in VO2max accounted for 59% of the difference in marathon times between men.
In a race between two trained runners with the same VO2max, however, differences in running economy (which can vary by up to 30% in people of similar VO2max) may instead decide who crosses the finishing line first.
Importantly, for those of us looking to improve our running performance, each of the three factors can be targeted with different types of training.
Strength training, plyometrics, and hill running are all shown to be particularly effective for improving our running economy. These forms of training allow us to run more efficiently by, among other things, increasing tendon stiffness and strengthening the communication between our nerves and muscles.
For improving your lactate threshold, tempo runs and interval training can improve your ability to clear lactate, allowing you to sustain higher running speeds for longer.
Intervals are also the key to improving your VO2max, although, as we’ll discuss later, some of us may reap greater benefits than others.
How do I improve my VO2max through training?
High-intensity interval training (HIIT) seems to be the ticket to a higher VO2max.
A 2013 meta-analysis, which collated the findings of 37 different studies, found that HIIT increased VO2max by about 500 ml O2 per min on average. For a 100 kg man with a baseline VO2max of 40 ml/min/kg, this figure would correspond to a new and improved VO2max of 45 ml/min/kg after HIIT (assuming he stayed the same weight).
To put these numbers in context, an untrained person typically has a VO2max in the range of 26-40 ml/min/kg (depending on sex and age). A recreational runner with some training under their belt may push their VO2max into the high 40s and 50s, whereas highly-trained, top-class marathon runners typically have a VO2max between 70 and 85 ml/min/kg. And then there are superhumans like ultrarunner Killian Jornet, who boasts a VO2max of 92 ml/min/kg!
So, high-intensity interval training (HIIT) seems to be particularly effective at raising VO2max, but what does a typical HIIT session look like?
Lots of different exercise protocols fall under the banner of HIIT, but they invariably involve short bouts (“intervals”) of exercise performed at high intensity (typically over 80% of your maximum heart rate) punctuated by periods of rest.
For runners: think of laps around a track or hill sprints, performed at high pace, high effort, and at 85-95% of your maximum heart rate (HRmax). Follow this with a recovery period of jogging or walking, where your heart rate can recover a little. Then repeat.
Intervals that are longer than 2 minutes seem to be the best for increasing VO2max, with 3-5 minutes being the likely sweet spot. On that note, in the aforementioned meta-analysis, the 9 studies recording the biggest increases in VO2max (around 850 ml per min) all involved intervals of 3-5 minutes.
Differences in VO2max response to training
Before you get lofty ideas of doing intervals and then keeping pace with Eliud Kipchoge, there’s an important caveat to the findings regarding HIIT and improvements in VO2max. As illustrated in the graph below, there is considerable variation between individuals in terms of VO2max response to HIIT (as well as other forms of endurance training).
While the bulk of us increase VO2max to a moderate degree, some lucky people, dubbed “high responders” seem to have much greater VO2max gains in response to training. By contrast, “low responders'', despite putting in exactly the same amount of training, may only nudge their VO2max upwards a little. This difference in the ability to improve VO2max in response to training is known as VO2max trainability.
One of the seminal studies to look at VO2max trainability was the Health, Risk Factors, Exercise Training, and Genetics Family Study - more catchily called the HERITAGE Family Study. Conducted between 1992 and 2013, the HERITAGE study measured the baseline VO2max of 813 sedentary-but-otherwise-healthy individuals from across 99 different families, before putting them through a 20-week endurance training programme.
The training programme involved 3 sessions a week on a stationary bike, with subjects progressively increasing the duration and intensity of their cycling workouts every two weeks. For the final six weeks, subjects were expected to cycle for 50 minutes per session at 55% of the heart rate associated with their baseline VO2max.* In this respect, rather than a one-size-fits-all approach, the training program was tailored to each individual’s baseline fitness. At the end of the 20 weeks of training, subjects’ VO2max was reassessed.
The results? There was wide variation in how much people improved their VO2max.
On average, subjects in the HERITAGE Family study improved by around 400 ml/min. As illustrated in the graph above, however, about 7% of people struggled to increase their VO2max by 100 ml/min or more. These people could be considered to be “low responders”. At the other end of the spectrum, roughly 8% of subjects improved their VO2max in excess of 700 ml/min - firmly in “high responder” territory.
But, what determined whether someone was a high, low, or average responder? About half of the answer seemingly involves genetics.
*Note that the HERITAGE study involved continuous (or so-called “steady-state”) exercise performed at moderate intensity, rather than the short bouts of high-intensity (85-95% of max heart rate) exercise that characterise HIIT. Nevertheless, differences in VO2max trainability have been widely shown in both types of training.
What causes differences in VO2max trainability?
One of the fundamental questions in life is: nature or nurture?
Most often, the simple answer is: both. Your height, for example, is strongly influenced by the genes you inherit from your parents (“nature”), but also depends on other environmental factors such as your diet (“nurture”).
Scientists are able to tease out the relative contributions of genes and environment to a trait (e.g. height, eye colour, IQ, VO2max trainability) by studying people who are genetically-related and then observing how much they differ with regards to that trait.
The ultimate example of people who are genetically-related is identical twins (known as monozygotic twins), who share 100% of their genes. Fraternal (or dizygotic) twins, by contrast, only share 50% of their genes. If genes play a large role in a trait, say height, we would expect identical twins to much more closely resemble each other in height compared to fraternal twins. Using this reasoning and some clever maths, scientists are then able to calculate something known as the heritability: the proportion of differences in a trait (e.g. height) that are attributable to genetic differences.
For height, heritability is estimated to be around 80%. In other words: 80% of the difference in height between individuals is due to genetic differences. This chimes with our deeply held intuitions: taller couples tend to have taller children and your height is strongly influenced by your genetics.
And so to VO2max trainability… Although the HERITAGE Family study didn’t strictly involve pairs of identical and fraternal twins, it did involve several families: mothers, daughters, fathers, sons, cousins etc., all of whom share varying amounts of genes.
If VO2max trainability had a significant genetic influence, we would expect people related within the same family to have more similar VO2max responses to training compared to unrelated people from different families.
After crunching the numbers from the HERITAGE study, it turns out that VO2max trainability has a heritability of 47%. Other studies report similar findings: about half of the differences in VO2max response to training are due to genetic differences.
Alas, heritability figures only tell us that genetics play a role in VO2max trainability, providing us with a rough idea of how much they contribute to differences between individuals. They do not identify the specific genes that affect VO2max trainability, nor do they shed any light on how individual (or groups of) genes might affect someone’s VO2max response to training.
Enter genotyping (the kind of DNA analysis that underpins your FitnessGenes results). This involves looking at particular regions of your DNA code to identify specific gene variants that you carry.
Such gene variants typically arise from SNPs (Single Nucleotide Polymorphisms) - single-letter changes in the DNA code that are common in the population. For example, where you might have the letter ‘T’ at one point in the DNA code of a particular gene, someone else might have the letter ‘A’ at the same point. While often having no discernible effect on the way your body functions, certain SNPs (and their associated gene variants) may sometimes have small but far-reaching effects on complex traits, such as your height, intelligence, or, indeed, your VO2max response to endurance training.
Now, if a particular SNP or gene variant seems to enhance VO2max trainability, we may expect to see this variant or SNP more frequently in people who improved their VO2max a lot in response to training - i.e. the “high responders.” Conversely, SNPs or gene variants that possibly impair VO2max trainability would be expected to occur more frequently in “low responders.” By identifying and comparing the frequency of different SNPs/gene variants in this way, we can then get a sense of which individual genes affect VO2max trainability, and how much of an influence they exert.
Using such genotyping techniques in HERITAGE study subjects, researchers identified 21 key SNPs / gene variants that were associated with VO2max trainability. Taken together, these 21 SNPs seemed to account for 49% of the differences in VO2max trainability between individuals.
To explore things further, the researchers gave people a score based on how many copies of each SNP/gene variant they carried. As shown in the graph below, people with a higher predictor SNP score tended to have greater increases in VO2max following the 20 weeks endurance training.
Subsequent studies have identified lots of other gene variants that seem to either enhance or impair your VO2max trainability. In isolation, each of these genes likely has only a small effect on your response to training, but, taken together, they may go some way to determining whether you’re a low, average, or high responder.
And, what do these genes have in common? They all seem to influence aspects of our body’s ability to develop adaptations to endurance training.
How do VO2max trainability genes affect your body’s adaptations to training?
All those hours spent logging miles on Strava, running laps of a track, or doing squats in the gym expose our cardiovascular, respiratory, and muscle energy systems to stress.
Try running as fast as you can for 800m. As you’ll no doubt have experienced, your heart had to pump harder and faster to supply your exercising muscles with oxygen and nutrients. These increased demands on your heart muscle and the force of higher blood flow through your arteries subjects your cardiovascular system to various forms of mechanical stress.
Similarly, your leg muscles suddenly had to carry out dozens of chemical reactions to quickly generate the energy used to propel you forwards for 800 metres. These reactions create byproducts (metabolites) such as lactate, phosphate, and hydrogen ions, which alter the chemical environment of muscle cells and subject them to metabolic stress.
When our body is regularly exposed to these types of stress through endurance training, it begins to adapt. In order to pump out more blood to supply exercising muscles, your heart increases in size and becomes better able to contract. In technical terms, we say your stroke volume (the amount of blood pumped out with each heartbeat) and cardiac output (the amount of blood pumped out by your heart in a minute) increase.
To better provide your muscles with blood containing oxygen and nutrients, new blood vessels grow and the density of capillaries in your muscles increases.
To cope with the increased energy demands of endurance exercise, your muscle energy systems adapt. Muscles increase their content of mitochondria - those “powerhouses of the cell” that allow you to generate energy - and enhance the activity of enzymes involved in energy production. Similarly, your muscles become more adept at using oxygen to burn fat for energy.
The denouement of these types of adaptations is that your cardiovascular and respiratory systems become more effective at taking oxygen from the atmosphere and delivering it via your bloodstream to exercising muscles. Correspondingly, your muscles also become better at extracting oxygen and using it to generate energy for movement. Sound familiar? This improved ability to deliver and extract oxygen is neatly encompassed by a higher VO2max.
When it comes to the genes linked to VO2max trainability, several of these are thought to play a role in the development of the endurance adaptations that we’ve just discussed.
The AMPD1 gene, for example, encodes an enzyme involved in your muscles’ generation of energy. ACSL1, another gene linked in multiple studies to VO2max trainability, is thought to affect your muscles’ capacity to use oxygen for burning fat for energy.
Although much more remains to be found out, it is possible that the genes linked to differences in VO2max trainability alter your ability to develop adaptations that enhance the delivery and extraction of oxygen. Whereas low responders may have a weaker genetic propensity to lay down such adaptations, high responders, by virtue of their genetics, may be pre-programmed to develop them more readily in response to training.
So, while it was a budget of six million dollars that constrained Steve Austin’s ability to become “better than he was before,” in our case, it’s our genes.
Image References
Bacon AP, Carter RE, Ogle EA, Joyner MJ. (2013) VO2max trainability and high intensity interval training in humans: a meta-analysis. PLoS One. Sep 16;8(9):e73182
Billat, V. L., Demarle, A., Slawinski, J., Paiva, M., & Koralsztein, J. P. (2001). Physical and training characteristics of top-class marathon runners. Medicine and science in sports and exercise, 33(12), 2089–2097.
Bouchard C, Sarzynski MA, et al. (2011). Genomic predictors of the maximal O₂ uptake response to standardized exercise training programs. J Appl Physiol. 110(5):1160-70.
Kim, D. S., Wheeler, M. T., & Ashley, E. A. (2022). The genetics of human performance. Nature reviews. Genetics, 23(1), 40–54.
Sarzynski, M. A., Ghosh, S., & Bouchard, C. (2017). Genomic and transcriptomic predictors of response levels to endurance exercise training. The Journal of physiology, 595(9), 2931–2939.
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