Genes & Exercise Performance

Learn about our understanding of genes and their relationship to genetic determinants among multiple interactions between genes and environmental influences that affect performance.

Exercise Physiology | Muscle Contraction | Muscle Fibers | Muscle Adaptations | Exercise Fuels | CHO Metabolism | Fat Metabolism | Oxygen Uptake | Cardiovascular Exercise | Respiratory Responses | VO2 Max | Temperature Regulation | Heat | Fluid Balance | Fatigue | Sprinting | Endurance | Genes | Practical Case Example

Genes & Exercise Performance 

Learn about how genes, progress in molecular biology, implications for genetics and advances our understanding of how the body adapts to exercise and how each of these contributions urges exercise physiologists, exercise scientists, and exercise professionals, to develop science-based exercise programs for athletes to improve performance. This module concludes the series developed to answer the question; are champions born or are they made?

Our final module is on genes and exercise performance. There’ll just be the one lecture this week and some small readings to give you some time to finalize preparation for the last test. It’s been known for hundreds of years that many biological traits are inherited. Whether it’s in plants, animals, or indeed humans.

Genetics & DNA 

The identification of DNA as the carrier of genetic material in the early 50s really then led to an explosion in our understanding of genetics, molecular biology, and greater insights into the link between genetics and disease. And that, of course, has extended into the investigation of the links between genes and exercise performance. And the question, are athletes born or are they made? The early approaches in this field looked at comparisons of twins, maximal oxygen uptake, and indeed some of the later studies looking at muscle fiber type. You can see in this early study, comparing the VO2 max values of twin A and twin B for monozygotic twins a very close association. With a little more scatter with the dizygotic twins, suggesting a large degree or heritability of this VO2 max. In fact in this study, they suggested that heritability could be as high as 80 to 90%.


  1. Heritability of VO2 Max – Heritage Family Study
  2. Angiotensin Converting Enzyme (ACE) [1] Genotype & Physical Performance
  3. ACTN3 [2] Genotype & Athletic Performance
  4. Genes & Power Performance
  5. Genes & Endurance Performance
  6. Variable VO2 Max Response to Training – Heritage Family Study
  7. Exercise & GLUT4 Gene [3]Expression
  8. Epigenetic Modulation of Gene Expression
  9. MicroRNAs & Muscle Adaptation
  10. PGC-I Alpha [4] Over-Expression, Muscle Oxidative Capacity & Exercise Tolerance
  11. Gene Delivery Goes Global
  12. World Anti-Doping Authority (WADA) Prohibited List

Heritability of VO2 Max – Heritage Family Study 

In a more recent study, the Heritage Family Study, a multi-centered trial, really a classic study in exercise science that brought together exercise physiologists and geneticists to really look at the relationship between families, genes, and some exercise-related variables. If you looked at the pre-training sedentary VO2 max values, there’s a familial aggregation of VO2 max. And you can see here a heritability estimate of about 51%. So clearly, there is a large genetic component to many of the physiological variables that influence performance. And, of course, one of the major determinants of athletic performance is sex. And we know that that’s very much determined by the genes that you inherit from your parents.

Angiotensin Converting Enzyme (ACE) Genotype & Physical Performance 

There is interest in determining if can we identify genes or even polymorphisms within genes that might predict or help us predict success in certain types of exercise performance. One of the early candidates was the ACE gene or the angiotensin-converting enzyme gene. And if you think about the biology of angiotensin renin, it’s involved with cardiac and cardiovascular physiology. And this study showed a relationship between the various alleles in this gene and performance, at least measured in climbers. And you can see that the more athletic climbing group had a greater frequency of the II genotype. And this was associated with an ability to increase performance in relation to the intervention.

ACTN3 Genotype & Athletic Performance 

The other gene that’s received the most attention is perhaps the one that is most successfully linked with measures of athletic performance is the alpha-actinin-3 gene. Now, alpha-actinin-3 is a protein that’s involved in the cytoskeleton, if you like, of skeletal muscle, and it really is a gene for speed that’s what is being termed. And you can see in the study from the Australian Institute of Sports Athlete Group, the XX characteristic which was the accommodation of the XX which was associated with an alpha-actinin deficiency. You can see that they tended to be more of that in the endurance type athletes and none of that combination in the power or sprint athletes. And so, it’s possible that perhaps the alpha-actinin-3 gene might be involved in some way. The challenge with all of these is the ability to predict the athletic potential from a single gene test. And I think, as we all suspect, exercise performance is very much a polygenic characteristic determined by not just multiple interactions of multiple genes, but also multiple interactions between genes and environmental influences. And we’ll come back to that point in a moment.

Genes & Power Performance 

One way to look further is to try and see if there are collections of genes that might predict power and endurance. And here, obtaining a total genotype score from the frequency of various genes which might collectively contribute to say sprint performance or endurance performance. So in this case, you can see a collection of genes that have been associated with power-oriented sports. The ACE gene, the alpha-actinin-3 gene, angiotensinogen, myostatin, which is a growth-related factor, interleukin 6, and nitric oxide synthase. And you can see that yes, while the power athletes had a significantly higher genotype score, you can see that there was significant overlap, and again reinforcing the notion of the polygenic nature of performance together with the interaction of the environment.

Genes & Endurance Performance 

Similar thing for endurance type sport, this time focusing on some of the genes that have been shown to be involved in mitochondrial biogenesis. And as we saw in the endurance performance lecture, there is a close association between muscle oxidative capacity and endurance performance. So that, it’s likely to think that something related to mitochondria biogenesis, or genes related to mitochondria biogenesis, might have some association with performance. And here we have Nuclear Respiratory Factor 2, Peroxisome Proliferator-Activated Receptor Alpha (PPARA), Peroxisome Proliferator-Activated Receptor Delta (PPARD), and Peroxisome Proliferator-Activated Receptor Gamma, Co-activator 1 Alpha (PPARGC1A), involved in mitochondrial biogenesis. Again, the genotype score, and yes, the endurance athletes had a significantly higher value. But again, you know, a great deal of overlap.

Variable VO2 Max Response to Training – Heritage Family Study 

Another aspect is there a genetic basis for the adaptations to exercise. So not only the intrinsic value, if you like, but in terms of response to training. And here again we go to the heritage study, and they showed that in response to standard 16-week exercise intervention, there was a quite a degree of variability in the response to that standard training program. When they looked at from a genome association study, a number of polymorphisms that were associated with the trainability, and connected those polymorphisms together and grouped them with those that had fewer than 9 and greater than 19. You can see that the more of those genes that you had, the greater was the VO2 training response. So clearly, there are many genes that are likely to contribute to this response. But the fact that there are some and there seems to be this relationship, suggests some degree of a genetic basis to the variability in the VO2 max response to training that was observed.

So, here is a figure from a very good review or article looking at the interactions between genetics and the environment in determining athletic performance. And you can see there are many factors which are going to influence performance which is determined by nature if you like, the genetic basis. Sex, height, VO2 max train abilities, skeletal muscle characteristics, and other relevant traits are going to have heritability indices which vary. And some of these you can see based on some of the literature the proportion that might be attributed to some of these polymorphisms. In parallel with that, you can see many of the factors which are influenced or which would influence perhaps the expression of that genotype. So, early exposure to physical activity, early exposure to certain environments, for example, altitude. And so, in relation to some of the debates around the success of the East African athletes is that a genotype factor, or is it related to early exposure to regular physical activity, to altitude exposure. There may be many other things that contribute to that. Coaching, training techniques, access to facilities, and all of the things are going to work together. And so, the champion is going to come from the pool of elite athletes. But which in turn is going to be influenced by the variable combinations of the genetics and the training environment.

And so, while I think there’s no question that successful athletes made to choose their parents carefully, they need to work hard and take full advantage of all of the opportunities they have to maximize their genetic potential. So are champions born or are they made? Well, they’re probably born and made.

Exercise & GLUT4 Gene Expression 

Just to finish on a few aspects of exercise and genetics, we know that exercise can affect gene expression. If you remember back to the lectures on the muscle adaptations to exercise, a single bout of exercise can impact gene expression. And here is from my particular research interests in the regulation of the glucose transporter the GLUT4 gene in muscle. Here is a single bout of exercise that increases the expression of GLUT4 at the gene level in skeletal muscle, and that continues during the recovery period. And as I showed you, in that lecture, a number of factors and signaling processes which can impact on gene expression. So, factors related to energy balance AMP kinase, factors related to calcium, all impact on transcription factors that influence the expression of the GLUT4 gene.

Epigenetic Modulation of Gene Expression 

One of these is an enzyme that’s involved in histone regulation. And this raises the issue of what we call epigenetics or modifications to gene expression that are not dependent on changes in the nucleotide sequence. And this is where environmental influences potentially can exert themselves. And so, it’s possible the gene expression can be altered, not through any change in the nucleotide sequence, but through changes in the modulation of structures and molecules around the gene. So, in the case of DNA, it’s surrounded by proteins known as histones. And these histones can be modified, they can be methylated, acetylated, phosphorylated, and in fact, the GLUT4 adaptation to exercise involves the phosphorylation of a histone deacetylase enzyme which results in increased acetylation of the GLUT4 promoter region. So, it’s possible that exposure to exercise, exposure to various environmental stimuli, can modify gene expression, not through altering the nucleotide sequence. And this is how environmental influences might modify gene expression. Some of these will be transient, some of them can be maintained for quite some time. The question then is, can they pass onto the next generation? And there’s a lot of activity in this space at the moment.

MicroRNAs & Muscle Adaptation 

Another aspect of the regulation of gene expression relates to non-coding pieces of RNA, referred to as microRNA. And it’s known that these microRNAs can influence gene expression and the ultimate phenotype. And the variation in the labels of these microRNA’s might be implicated in some of the adaptive responses, and indeed might alter gene expression and, and the ultimate phenotype. So here’s an example where strength training was examined in a group of healthy volunteers, and just as was seen in the heritage study with variability in VO2 max, there was variability in the increasing lean body mass with the strength training program. There were lower responders, and there were higher responders. If you then look at the microRNA profile of the low and high responders, you could see here that the low responders had increased levels of this microRNA in the muscle known as 451. Whereas the high responders had very low levels. So, perhaps something about having an elevated level of this particular MicroRNA attenuated the strength training adaptation in that group of subjects. So, there has been a lot of interest in these various non-genomic modifications of gene expression and phenotype.

PGC-I Alpha Over-Expression, Muscle Oxidative Capacity & Exercise Tolerance 

Another aspect of exercise and genes is the ability to manipulate gene expression, and in so doing manipulate characteristics of muscle and exercise performance. And there are a number of examples now where single genes have been introduced into the muscle to affect performance. So notwithstanding my earlier comments about exercise performance being the result of many factors and polygenic influences. It has been shown in a number of studies that if you increase the muscle expression of certain proteins, in this case, PGC-1 alpha (PPARGC1A), activated metalloproteinase thrombospondin (METH2), heat shock protein 70 (Hsp70s), and peroxisome proliferator-activated receptor delta (PPRdelta). That associated with changes in the metabolic and oxidative capacity of the muscle and in endurance performance. So here’s just one example where transgenic mice were manipulated, and there was an increase in the muscle expression of PGC-1 alpha. Now, this transcriptional co-activator is involved in the regulation of mitochondrial biogenesis, and angiogenesis. And these transgenic mice in many respects, take on the characteristics of mice that have been exercise trained. If you compare the muscle oxidative capacity in this case, through measuring cytochrome B significantly higher muscle oxidative capacity in this transgenic mouse. And when they were put on a treadmill to run, you can see that there was an improved endurance performance in these transgenic mice.

Gene Delivery Goes Global 

These are the sorts of studies that really cause some concerns around the regulatory authorities who are trying to regulate and stamp out doping in sport. Because it is technically possible to introduce some of these vectors, either directly into the muscle, or in this case, systemically. And here’s an example where there is research in the muscular dystrophy area, which is designed to try and improve the lives of young boys who suffer from this terrible muscular disease. And this disease results from a lack of protein known as dystrophin. It’s one of the largest proteins in muscle and using adeno-associated with viruses (AAV), it’s possible to introduce a microdystrophin and target it to skeletal muscle. Now, you can imagine, and you can see here that when that was done, the green stain here is the injected animal that normally lacks dystrophin. You can see here in the untreated mouse, but quite a good expression both in muscle and in the heart of this protein that was normally missing. And of course, this raises the specter of what’s been called gene doping, where you might inject various constructs into the muscle or systemically to try and alter the physiological metabolic characteristics of tissues with the ultimate aim of trying to improve performance.

World Anti-Doping Authority (WADA) Prohibited List 

So as I said, it’s, it’s these sorts of studies, where the introduction of genes into specific tissues or into the body can impact performance. That has led the World Anti-Doping Authority to specifically ban gene doping, just as it’s banned the administration of various growth factors and other pharmacological agents such as [anabolic] steroids. So, as I said, there’ve been remarkable advances in molecular biology since the isolation and characterization of DNA — The Human Genome Project and these have far-reaching implications for our understanding of genetics and disease, and also our understanding of how the body adapts to exercise. But the dark side of the increase in knowledge is the potential for it to be used illegally in attempts to try to improve sports performance.[18].

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    Genes and Exercise Performance was last modified: October 12th, 2019 by Derek Curtice