ACTN3 Gene: Deficiency and Muscle Type

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 may be right! At the most elite level, the ACTN3 gene impacts athletic performance due to changes in the type of muscle fiber.

This article digs into the research on the ACTN3 gene, including 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 does the ACTN3 gene do?

The ACTN3 gene encodes actinin alpha-3, a protein found in fast-twitch muscles. Fast-twitch muscles are responsible for explosive bursts of power or speed.

A common genetic variant in the ACTN3 gene causes about 20% of the population not to produce fast-twitch muscle fibers.

First, let me give you a quick overview of how muscles work, and then I’ll go into the research studies specific to the ACTN3 protein.

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 forms the thicker strands.

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

 

Zooming in 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 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 to learn what happens with ACTN3 deficiency.

They found that mice without the ACTN3 protein could 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 fairly common genetic change 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. This correlates to ACTN3 rs1815739 TT

The RR genotype means that you have two copies of the functioning ACTN3 gene (rs1815739 CC).

In between those two genotypes is rs1815739 CT. More on what this all means and how to check your genetic data in the Genetic Variants section below. 

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]
  • Older people who have the functional ACTN3 gene may have a (slight) advantage in maintaining muscle mass, which decreases the risk of falls.[ref]

Lower bone mineral density: The ACTN3-deficiency genotype has links to lower bone mineral density (BMD) in postmenopausal women. The difference was about 1% lower BMD for women with the XX genotype.[ref]

Other studies have replicated this finding. The slightly lower muscle mass in people with the ACTN3-deficiency variant likely leads to less load-bearing activities daily.[ref]

Mouse studies show ACTN3 is expressed in osteoblasts (cells that form bone). ACTN3-deficiency 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 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 benefit 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 focus on the connection with athletic performance.

More recent studies have investigated how muscle fiber composition changes affect aging, muscle metabolic function, and osteoporosis.

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

Studies on ACTN3 in bodybuilders and performance athletes: Sprinter Genes

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. It was in stark comparison to the ~30% of Olympic endurance athletes carrying the ACTN3-deficient genotype.[ref]
  • Studies 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 produced ACTN3 had a much lower risk of acute ankle sprains.[ref

ACTN3-deficiency and lower creatine kinase:
People with the ACTN3-deficient (XX) genotype had lower creatine kinase levels at baseline. Resting creatine kinase levels are usually higher in athletes and 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 three times more likely to have exertional rhabdomyolysis, a serious (and fairly rare) condition where the muscles break down. This death of muscle tissue causes the release of protein into the bloodstream, affecting 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 show 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 levels in between the mice with two copies of the functional ACTN3 gene and the mice with 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 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 theorize that there must be a reason 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 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 shivering as much (and thus used 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 it confers a survival advantage for infants in cold weather.


Here’s how to check your ACTN3 gene:

Members: Log in to see your data below.
Not a member? Join here. Membership lets you see your data right in each article and also gives you access to the member’s only information in the Lifehacks sections.

 

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?

There are big differences in the prevalence of the ACTN3 variants based on ancestry.  For example:

  • About 25% of Caucasians have the ACTN3-deficient (TT) genotype.
  • 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]

ACTN3 Supplement:

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 two 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 than the athletes carrying the functional allele.[ref]

The pequi oil research indicates that antioxidant supplementation may be more effective for the ACTN-3 deficient genotype.

Bruxism (teeth grinding), ACTN3, and jaw muscles:

A recent study found that people who grind their teeth (bruxism) and also have the ACTN3 functional allele (CC) are likely to have larger jaw muscles than patients without the functioning ACTN3 (CT and TT). [ref]

Related article: Teeth grinding and your genes

The rest of this article includes information on genetic interactions and avoiding injuries with ACTN3. It is for Genetic Lifehacks members only.  Consider joining today to see the rest of this article.

Interaction between ACTN3 and ACE genotypes:

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About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.