The ACTN3 gene codes for actinin alpha-3, a protein found in muscles.
First, let’s take a quick minute to go over how muscles work… (skip ahead if you know this stuff)
Skeletal muscles attach to your bones and help you move and stabilize your joints. In addition to movement, your skeletal muscles also stop movement, resisting gravity and other forces. They are constantly working, even when you are still.
When your muscles use ATP for energy, they produce heat. This is why you get hot when you exercise — and why you shiver (tiny muscle contractions) when you are cold.
Your skeletal muscles are made up of muscle fibers, blood vessels, nerve fibers, and connective tissue. The muscle fiber is made up of functional units called sarcomeres, which contain the filaments actin and myosin.
Actin forms the thinner strands of the sarcomere and myosin form the thicker strands.
Here is a quick video showing how muscles contract:
Zooming in even further, there are several types of actin proteins, one of which is coded for by the ACTN3 gene. The actinin alpha 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 fibres, which are responsible for producing ‘explosive’, powerful contraction”. [ref]
These are the types of muscle contractions needed in power sports such as deadlifting, sprinting, speed skating, and short distance cycling.
Researchers created a mouse strain that lacks the ACTN3 gene as a way of learning what happens with ACTN3 deficiency. They found that the mice without the ACTN3 protein were able to run about 33% long (similar to an endurance athlete). Most of the other parameters were the same for the mouse muscles, but the researchers did find that the twitch half-relaxation time of the ACTN3-deficient muscles was 2.6 ms longer.[ref]
There is a common variant in the ACTN3 gene that causes some people not to have this protein. Studies refer to this variant 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.
Check your genetic data for rs1815739 (23andMe v4, v5; AncestryDNA):
About 25% of Caucasians have the ACTN3-deficient genotype, but less than one percent of some African populations carry the ACTN3-deficient genotype. [ref] Other populations vary between those numbers, with a worldwide average of 18% of people carrying the ACTN3-deficient genotype.
There are tons of 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.
A study using biopsies of human muscles found that those with the ACTN3-functional genotype had more of the type IIx muscle fiber (fast twitch glycolytic). [ref]
A big study published in 2003 found that no Olympic power athletes carried the ACTN3 deficient genotype. This was compared with about 30% of the Olympic endurance athletes carrying the ACTN3-deficient genotype. [ref] Of course, headlines about ‘athletic genes’ ensued.
There were many subsequent studies on athletes and the ACTN3 gene with varying results. Some results showed there was no significant difference in athletes when comparing the ACTN3 genotype. [ref][ref][ref] Other studies found that the difference only existed for elite female athletes. [ref]
A study found that athletes with the RR (produces ACTN3) genotype had a much lower risk of acute ankle sprains. [ref] The connection with ankle sprains may be population specific since it was only found in Chinese cohorts. A large study on ankle sprain genes done in the US did not find that ACTN3 was statistically significant.[ref]
ACTN3-deficiency and lower creatine kinase:
A study found that people with the ACTN3-deficient (XX) genotype had lower creatine kinase levels at baseline. Resting creatine kinase levels is usually higher in athletes and those 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 muscle tissue into the bloodstream, which then can affect the kidneys. [ref]
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), mouse studies do show that there is a minor difference.
The mice that were heterozygous (one copy) had an endurance that was 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]
As we age, we tend to lose muscle mass, starting around age 25. This muscle loss due to aging is called sarcopenia.
More falls, less lean body mass:
Elderly people with the ACTN3-deficient genotype may have more falls.[ref] Another study found that lean body mass was lower in women with the ACTN3-deficient genotype. [ref]
In general, 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 also been tied to decreased bone mineral density in post-menopausal 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 that ACTN3 is expressed in the osteoblasts (cells that form bone). ACTN3-deficiency then could lead directly to slightly reduced bone mineral density. [ref]
Muscle tissue can function aerobically, burning glucose with plenty of oxygen, or they 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.
It has been discovered, through mouse models and human testing, that the ACTN3-deficient genotype shifts the muscles towards more aerobic metabolism, which may be beneficial for endurance athletes. [ref]
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]
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 indicates that antioxidant supplementation may be even more effective for people who carry the ACTN-3 deficient genotype.
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 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]
If you are at the top of your sport and looking to optimize, genetics does come into play with muscle composition and endurance.
Do you end up getting sore after pretty much every work out at the gym? It could be that a deficiency caused by the AMPD1 genetic variant is the cause.