The Evolution of ACTN3 – Discovery of the Sprint Gene

“Though the ACTN3 gene does appear to influence sprinting ability, making a sports decision based on it is like deciding what a puzzle depicts when you’ve only seen one of the pieces. You need that piece to complete the puzzle, but you certainly can’t see a meaningful picture without more pieces.” – David Epstein

There is over two decades worth of genetic research used in a variety of ways, from helping athletes understand themselves, to identifying risks for certain diseases. While there has been remarkable progress, this is only just the beginning of our understanding of genetics. New discoveries can lead to increased scientific confidence, or change our understanding completely. Many know ACTN3 as the “sprint gene” – something remarkable sprinters have to help them win gold medals.

But it didn’t start out this way.

In the 1990s, Dr. Kathryn North, pediatric physician and clinical geneticist, was searching across the human genome for the gene causing muscular dystrophy, a devastating muscle-wasting disease. She and her team found that about 1 in 5 of those with the disease were missing a muscular protein called alpha-actinin-3 (ACTN3). Before sharing with the world that she had found another gene for muscular dystrophy, she looked at carriage of the ACTN3 gene in diverse sets of populations across the globe.

What she found was much to her surprise: healthy people without muscular dystrophy also lacked the ACTN3 gene. Structurally, they understood that ACTN3 played a major role in muscle function, but instead of looking at the gene from a disease perspective, North and her colleagues analyzed people at the opposite end of the spectrum: those with extraordinary athletic ability.

North was right. In 2003, a study was published in the American Journal of Human Genetics showing that elite Australian sprinters were more likely to carry the ACTN3 gene than normal, healthy individuals (Yang et al., 2003). Fast-forward thirteen years and we can now predict 200 meter sprint times based on ACTN3 genotypes (Papadimitriou et al., 2016). The same study also showed that ACTN3 genotype accounts for around 1% of sprint time variance. Quite literally, your genotype at ACTN3 may be the difference between qualifying for the Olympics and winning a medal.

Tracing back the history of speed: selection for a non-functional ACTN3 gene

Dr. North was surprised to find healthy people that completely lacked a functional gene. In many cases, when someone lacks a functional copy of a gene – causing the gene to not make its intended protein product – disease can occur; as in the case of cystic fibrosis.

With the advent of genetic sequencing in the early 2000s, researchers were able to compare the genetics of diverse populations with a few clicks. We now know that worldwide, over 1.5 billion people lack ACTN3, mostly those with American and European ancestry (Amorim et al., 2015).

Why did these people evolve to lose a gene that made them faster?

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Population frequencies of ACTN3 from Ensembl.org

In comparison to our primate relatives, humans are relatively poor sprinters. Being a biped – an animal that uses two legs for walking – poses a significant disadvantage to humans in the context of sprinting. However, endurance running is unique to the human race, and we perform remarkably well at it compared to other species. This ability to run for long distances originated in the Homo species about 2 million years ago, coinciding with the earliest migrations of humans out of Africa (Bramble & Lieberman, 2004).

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Human migration map out of Africa. Courtesy of National Geographic, from the National Genographic Project. 

This idea of ACTN3 playing a role in adaptation to environmental pressures intrigued Dr. North after she first discovered the gene. She and her research team did experiments on transgenic mice that lacked ACTN3 to understand what happens at the molecular level when ACTN3 is not present. They demonstrated that the lack of ACTN3 in mouse muscle cells results in a shift of metabolism in fast twitch muscle fibers to the slower, but more efficient, aerobic energy system, normally associated with slow-twitch muscle fibers. Although the association between ACTN3 deficiency and endurance capacity in humans is unclear, the ACTN3-deficient mice in this study performed 33% better on average in an endurance capacity test (MacArthur et al., 2007).

This shift to a more efficient and endurance-oriented energy system might be the underlying explanation for why American and European populations have a significantly decreased distribution of ACTN3 compared to those of African descent. The aerobic-oriented metabolism in ACTN3 deficient muscle fibers may have given our ancestors an advantage in traversing land for long periods of time, causing the loss of ACTN3 to be naturally selected for as a genetic advantage. In those of us that ACTN3 persisted in, like 99% of Olympic sprinters, ACTN3 poses a significant advantage in the context of sprinting and power performance.

actn3-infographic-nov-23-01_timeline

What is the sprint gene and how does it work?

Your muscles are a set of molecular motors governed by the action of the muscle filaments actin and myosin. The efficiency of the interactions between actin and myosin in the muscle fibers of your body are what control the speed and power of how your muscles move. Actinin-alpha-3 (ACTN3) plays a role in muscle contraction by acting as a support protein to the actin filaments. It constitutes the main component of the Z-disc, a part of the muscle that separates each sarcomere, the basic unit of muscle fibers.

ACTN3 is found only in fast-twitch fibers, those that fire more quickly and generate more force compared to slow-twitch fibers.

When ACTN3 is not present in the muscle cell, another actinin protein compensates for its loss (Mills et al., 2001). This is called ACTN2, and is only found in slow-twitch muscle fibers, explaining the above mentioned shift in metabolism. When ACTN3 is completely absent in muscle cells (TT genotype), the Z-disc becomes less resistant to deformation during muscle contraction, causing a structural disadvantage. Therefore, muscle fibres may be less robust in TT individuals, and more susceptible to damage during high levels of eccentric strain and high impact movements.

How to apply ACTN3 understanding in training 

It is well-documented that ACTN3 is associated with elite sprint and power performance (Ahmetov & Fedotovskaya, 2015), but it’s not necessary to be one of the best. A notable exception to the gene for speed is highlighted in a 2007 case study of an elite Spanish long jumper who was completely deficient of ACTN3 (Lucia et al., 2007). It is important to note that ACTN3 genotypes should never be used for talent identification, as differences in the gene translate to only fractions of a difference in muscle contraction and firing speed.

With that being said, an improved understanding of your or your athlete’s genetics at ACTN3 can provide an improved basis for training recommendations when building a program. After a robust literature search, we have split our recommendations into structural and metabolic advantages for each set of ACTN3 genotypes.

Genotype Structural Metabolic
TT (ACTN3 deficient) Should ensure adequate recovery between bouts of high impact exercise and progressively increase the density of training in order to mitigate the increased risk of muscular damage. May have higher baseline aerobic status. May adapt slower to anaerobic-lactic training modalities and may be more suited towards excelling at aerobic training schemes compared to CC/CT individuals.
CT (One copy of sprint gene) May have an increased resistance to muscle damage. May be able to handle more dense workloads involving high impact/eccentric exercise compared to TTs. Improved ability to mobilize glycogen in fast-twitch muscle fibres. May excel in training schemes based heavily around the anaerobic-lactic pathway relative to TT individuals.
CC (Two copies of sprint gene)

The perseverance of researchers like Dr. North shows that genetic research will always be paramount to human health and performance. Where we start is not always where we finish: ACTN3 was originally thought to be a precursor for muscular dystrophy but lead to a discovery of it’s applicability in high performance sport. Chances are, this is not the last breakthrough for ACTN3 research. At Athletigen, we aim to push discovery further through partnerships with high performance athletes and world leaders in research.  

We are focused on taking the current findings of genetic research and being the first company to truly combine this information with an athlete’s ever-changing environment and allow for adjustments in training.  

Want to learn about how ACTN3 affects you?

FIND OUT WITH ATHLETIGEN

References:

Ahmetov, I. I., & Fedotovskaya, O. N. (2015). Chapter Six – Current Progress in Sports Genomics. In G. S. Makowski (Ed.), Advances in Clinical Chemistry (Vol. 70, pp. 247–314). Elsevier.

Amorim, C. E. G., Acuña-Alonzo, V., Salzano, F. M., Bortolini, M. C., & Hünemeier, T. (2015). Differing Evolutionary Histories of the ACTN3*R577X Polymorphism among the Major Human Geographic Groups. PLoS ONE, 10(2).

Bramble, D. M., & Lieberman, D. E. (2004). Endurance running and the evolution of Homo. Nature, 432(7015), 345–352.

Lucia, A., Oliván, J., Gómez‐Gallego, F., Santiago, C., Montil, M., & Foster, C. (2007). Citius and longius (faster and longer) with no α‐actinin‐3 in skeletal muscles? British Journal of Sports Medicine, 41(9), 616–617.

MacArthur, D. G., Seto, J. T., Raftery, J. M., Quinlan, K. G., Huttley, G. A., Hook, J. W., … North, K. N. (2007). Loss of ACTN3 gene function alters mouse muscle metabolism and shows evidence of positive selection in humans. Nature Genetics, 39(10), 1261–1265.

Mills, M., Yang, N., Weinberger, R., Vander Woude, D. L., Beggs, A. H., Easteal, S., & North, K. (2001). Differential expression of the actin-binding proteins, alpha-actinin-2 and -3, in different species: implications for the evolution of functional redundancy. Human Molecular Genetics, 10(13), 1335–1346.

Papadimitriou, I.D., Lucia, A., Pitsiladis, Y.P., Pushkarev, V.P., Dyatlov, D.A., Orekhov, E.F., Artioli, G.G., Guilherme, J.P.L.F., Lancha, A.H., Ginevičienė, V., et al. (2016). ACTN3 R577X and ACE I/D gene variants influence performance in elite sprinters: a multi-cohort study. BMC Genomics 17.

Yang, N., MacArthur, D.G., Gulbin, J.P., Hahn, A.G., Beggs, A.H., Easteal, S., and North, K. (2003). ACTN3 genotype is associated with human elite athletic performance. Am. J. Hum. Genet. 73, 627–631.

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