ACTN3 gene: Muscle type and athletic performance

When you look at a marathon runner next to a powerlifter, you can’t help but think that there must be a fundamental genetic difference between them. You could be right! At the most elite level, the ACTN3 gene impacts performance.

This article digs into the research on the ACTN3 gene including the research on athletic performance, cold adaptation, metabolic health and aging.   Don’t want to read the background studies? Jump ahead to check your genetic data for the ACTN3 gene.

What is the ACTN3 gene?

The ACTN3 gene encode actinin alpha-3, a protein found in fast-twitch muscles. Fast-twitch muscles are responsible for explosive burst of power or speed.  A common genetic variant in the ACTN3 gene causes about 20% of the population to not produce fast-twitch muscle fiber.

First, let me give you a quick overview of how muscles work…(skip ahead if you know this stuff)

Background science on muscles:

Skeletal muscles attach to your bones and help you move and stabilize your joints. In addition to movement, your skeletal muscles also stop movement, resist gravity, and other forces. They are constantly working, even when you are still.

Your skeletal muscles are made up of muscle fibers, blood vessels, nerve fibers, and connective tissue. The muscle fiber’s make-up contains functional units called sarcomeres. Each sarcomere includes the filaments actin and myosin.

Actin forms the thinner strands of the sarcomere and myosin form the thicker strands.

Here’s a quick video on how actin and myosin work in the muscle:

 

Zooming in even further, there are several types of actin proteins, one of which is coded for by the ACTN3 gene.

The ACTN3 (α-actinin-3) protein is only found in the fast-twitch muscle fibers. There is also an ACTN2 protein that is found in all muscle fibers.[ref]

One study explains: “The expression of α-actinin-3 protein is almost exclusively restricted to fast, glycolytic, type 2X fibers, which are responsible for producing ‘explosive’, powerful contraction”.[ref]

This type of explosive, powerful muscle contraction is needed in power sports such as:

  • deadlifting
  • sprinting
  • speed skating
  • short distance cycling.

What happens if you don’t have the ACTN3 protein?

Researchers created a mouse strain that lacks the ACTN3 gene as a way of learning what happens with ACTN3 deficiency.

They found the mice without the ACTN3 protein were able to run about 33% longer (similar to  a long distance runner). Most of the other parameters were the same for the mouse muscles, but the researchers did find the twitch half-relaxation time of the ACTN3-deficient muscles was 2.6 ms longer.[ref]

What about in people? A common genetic variant in the ACTN3 gene causes some people not to produce the ACTN3 protein. This variant is referred to as R577X. The XX genotype in studies refers to people who have the non-functioning ACTN3 gene, which means they do not produce the ACTN3 protein. The RR genotype means that you have two copies of the functioning ACTN3 gene.

ACTN3 affects muscles, aging, and longevity:

As we age, we tend to lose muscle mass, starting around age 25. This muscle loss due to aging is called sarcopenia.

Studies show that ACTN3 deficiency = More falls, less lean body mass:

  • Elderly people with the ACTN3-deficient genotype may have more falls.[ref]
  • Lean body mass is lower in older women with the ACTN3-deficient genotype.[ref]
  • Elderly people who have the functional ACTN3 gene may have a (slight) advantage in terms of maintaining muscle mass, which decreases the risk of falls.[ref]

Lower bone mineral density: The ACTN3-deficiency genotype has links to decreased bone mineral density in postmenopausal women. The difference is about 1% less BMD for women with the XX genotype.[ref] Other small studies have replicated this finding. It is likely that the slightly lower muscle mass in people with the ACTN3-deficiency leads to less load-bearing activities on a daily basis.[ref]

Mouse studies show ACTN3 is expressed in the osteoblasts (cells that form bone). ACTN3-deficiency then could lead directly to slightly reduced bone mineral density.[ref]

ACTN3 and metabolism:

Muscle tissue can function aerobically, burning glucose with plenty of oxygen, or it can function anaerobically, relying on lactic acid. Anaerobic respiration is quick and doesn’t need oxygen, but it also doesn’t produce as much ATP.

Discovered through mouse models and human testing, the ACTN3-deficient genotype shifts the muscles towards more aerobic metabolism, which may be beneficial for endurance athletes.[ref]

What do research studies show on ACTN3?

There are tons of research studies on this gene, and most of the initial studies focused on the connection with athletic performance.

More recent studies, though, have investigated how the change in muscle fiber composition affects aging, muscle metabolic function, and osteoporosis.

Keep in mind that people with the ACTN3-functional genotype have more of the type IIx muscle fiber (fast-twitch glycolytic muscle).[ref]

Studies on ACTN3 in bodybuilders and performance athletes:

Large studies have investigated how the ACNT3 gene affects elite athletes:

  • A big study published in 2003 found that no Olympic power athletes carried the ACTN3 deficient genotype. This was in stark comparison to the ~30% of Olympic endurance athletes that do carry the ACTN3-deficient genotype.[ref]
  • Studies do back the idea that the ACTN3-deficient genotype is found much less often in elite power athletes (sprinters, weightlifters, etc).[ref][ref][ref]
  • Other results showed there was no significant difference in athletes when comparing the ACTN3 genotype.[ref][ref][ref] One study found the difference only existed for elite female athletes.[ref]
  • Studies on elite team sports (e.g. soccer) athletes have found that there is usually a normal population mix of ACTN3 genotypes.[ref][ref]
  • A study found that athletes who produce ACTN3 had a much lower risk of acute ankle sprains.[ref

ACTN3-deficiency and lower creatine kinase:
People with the ACTN3-deficient (XX) genotype have lower creatine kinase levels at baseline. Resting creatine kinase levels is usually higher in athletes and in people with greater muscle mass.[ref] In fact, another study showed that people with the ACTN3-deficient genotype had 2% lower muscle mass on average. Not a huge difference, but it was statistically significant.[ref]

ACTN3-deficiency and rhabdomyolysis risk:
People with the ACTN3-deficient genotype are also about 3 times more likely to have exertional rhabdomyolysis, which is a serious (and fairly rare) condition where the muscles break down. This death of muscle tissue causes the release of protein into the bloodstream, which then can affect the kidneys.[ref]

The In-betweeners – ACTN3 CT vs CC:

While most studies don’t find a huge difference in people between having one copy of the deficiency allele (CT) vs having two copies of the normal allele (CC), animal studies do show that there is a minor difference.  Essentially, lab mice are a lot easier to control the variable for and see exactly what a gene variant may impact.

Mice with one copy of the deficiency allele had endurance in between the mice that had two copies of the functional ACTN3 gene and the mice that had two copies of the ACTN3-deficiency genotype.[ref]

Why is the ACTN3 variant so common? Cold tolerance…

The frequency of the ACTN3-deficiency genotype varies a lot by population group, with up to 25% of Caucasians being deficient compared to less than 1% of some African population groups.

While it seems that having the active ACTN3 gene would give an adaptive advantage for speed to our human ancestors, evolutionary biologists theorized that there must be a reason why such a high percentage of some population groups carry the ACTN3 deficiency genotype.

The answer to this question may lie in cold adaptation. New research shows that as our human ancestors migrated north out of Africa and the Middle East, there was an increase in the percentage of people who were ACTN3 deficient.

Researchers recently showed that people with the ACTN3-deficient (TT) genotype are better at maintaining their core body temperature in the cold.[ref]

The study involved healthy young (18-40) males. The men were immersed in cold water to lower their core body temperature to 35.5°C – or for a total of 120 minutes, whichever came first. The number of participants who maintained their core temperature above 35.5°C for 120 minutes of cold water immersion was calculated. Individuals with ACTN3-deficiency were twice as likely to complete the 120 minutes vs. people with ACTN3 intact (69% vs 30%). The researchers also found that people with ACTN3-deficiency maintained body temperature without using up as much energy.[ref]

What is going on with the ACTN3 muscle type and cold? The researchers showed that the increased amount of slow-twitch muscle fiber increased heat production without needing to shiver as much (and thus used a little less energy). While this is a nice advantage for adults in cold climates, it may be that the biggest driver of the mutation increasing in population groups is that is confers a survival advantage for infants in cold weather.


Here’s how to check your ACTN3 gene:


Members: Log in to view your data below.  Not a member? Join now.

Check your genetic data for rs1815739 (23andMe v4, v5; AncestryDNA):

  • C/C: functioning ACTN3, optimal for elite power athletes, more type IIx muscle fiber (RR)
  • C/T: functioning ACTN3, optimal for elite power athletes (RX)
  • T/T: non-functioning ACTN3 gene, more likely to be an endurance athlete than power athlete (XX)

Members: Your genotype for rs1815739 is .

How common is the ACTN3 variant?

About 25% of Caucasians have the ACTN3-deficient genotype.

This is in sharp contrast to less than 1% of some African population groups with the ACTN3-deficient genotype.[ref] Other population groups vary between those numbers, with a worldwide average of 18% of people carrying the ACTN3-deficient genotype.

 


Lifehacks for ACTN3:

What should you eat with the ACTN3 gene variant?

Mouse studies using a high-fat diet showed that the ACTN3-deficient genotype had less weight gain. But human studies don’t show a significant effect on obesity from ACTN3.[ref]

Supplements for ACTN3:

A study of Brazilian runners looked at the interaction between the ACTN3 gene and pequi oil supplementation. Pequi oil is rich in carotenoids (provitamin A and lycopene – antioxidants) and consists mainly of palmitic and oleic fatty acids.

The researchers compared the athletes’ baseline metabolite measurements with the results after 2 weeks of supplemental pequi oil (400 mg/day). Creatine kinase, which normally rises after exercise indicating muscle damage, was reduced after the antioxidant supplementation. The ACTN3-deficient athletes had significantly lower creatine kinase values after antioxidant supplementation compared with the athletes that carry the functional allele.[ref] This research indicates that antioxidant supplementation may be more effective for the ACTN-3 deficient genotype.

Interaction between ACTN3 and ACE genotypes:

The ACE gene codes for the angiotensin-converting enzyme, which is part of the RAS system that regulates blood pressure. There are lots of studies on a variant of the ACE gene (known as ACE deletion), blood pressure, and saturated fat consumption. Read more about the ACE gene. 

Interestingly, the ACE deletion/insertion variants are also associated in some studies with athletic performance, especially in conjunction with the ACTN3 genotypes.

Check your genetic data for rs4343 (23andMe v4, v5; AncestryDNA):

  • A/A: ACE insertion/insertion, lower ACE enzyme activity, (perhaps) better performance in endurance athletes.
  • A/G: normal response to saturated fat (heterozygous – ACE deletion/insertion)
  • G/G: ACE deletion/deletion, higher ACE enzyme activity, high saturated fat diet may increase blood pressure and risk of heart disease.[ref]

Members: Your genotype for rs4343 is .

A study of inactive adults found that at baseline, those with the ACE deletion/deletion genotype had higher lean body mass and BMI. After 10 weeks of leg extension exercise, those with the deletion/deletion genotype had greater muscle volume gains.[ref]

ACE Insertion + ACTN3 deficiency:
A study of swimmers found that the ACE insertion genotype combined with the ACTN3-deficiency genotype was beneficial for long-distance swimmers.[ref]

A meta-analysis of a bunch of studies showed that overall the results point to an advantage for the ACE insertion/insertion genotype for endurance athletes. This meta-analysis did not find a gene X gene interaction with ACTN3 or a positive association with the ACTN3-deficiency and endurance sports.[ref]

No impact for non-athletes:
Other studies in untrained, non-athletes found that there was no difference in gains from resistance training when comparing ACE and ACTN3 genotypes.[ref] The genotypes also did not vary in a group of Polish athletes.[ref] And a study of marathon runners also found no statistically significant difference between ACE and ACTN3 genotypes for the athletes.[ref]

ACE and Glucose response:
When it comes to dietary interventions, a study showed that ACE levels are not affected by glucose ingestion prior to intense exercise.[ref]

 

Article originally published May 2019, updated March 2021


Related Articles and Topics:

Top 10 Genes to Check in Your Genetic Raw Data
It can be overwhelming when you are getting started with learning how your genes affect your health. These are the ten important genes that I think everyone should take a few minutes and check.

Athletic Performance Genes
If you are at the top of your sport and looking to optimize, genetics does come into play with muscle composition and endurance.  Check out this article on other genetic variants that also impact athletic performance.

Sore Muscles – AMPD1 Deficiency
Do you end up getting sore after pretty much every workout at the gym? It could be that a deficiency caused by this AMPD1 genetic variant is the cause.

 



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering from Colorado School of Mines. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.