A natural mutation causes some people to not feel the cold

Over 80,000 years ago, Homo sapiens started leaving their African homeland to colonize the world. This great migration first brought them to far east Asia then, around 42,000 years ago, to Europe.

While they encountered frigid conditions, inevitably their metabolism evolved to adapt to a different climate. But this ability to withstand the cold is not distributed evenly. Over the last decade, scientists have sought to answer the age-old question of why some modern Homo sapiens have better cold tolerance as compared to others.

On Wednesday, a team announced in a study published in the American Journal of Human Genetics an answer. People lacking the alpha-actinin-3 protein in their muscle fibers can tolerate the cold better compared to those who do not carry this gene variant, the new research suggests.

Lacking this protein causes "superior cold resilience," the study team writes. This deficiency affects almost one in five people.

The background — In 2014, a study led by Marius Brazaitis, a scientist at the Lithuanian Sports University, and his team attempted to understand how the human body acclimates to severe cold exposure based on various parameters like stress hormones and metabolic activity. “But we found nothing,” he tells Inverse.

As Brazaitis and his team continued to carry out experiments, a 2013 PLOS One study helped them in uncovering the mystery behind some people’s superior cold tolerance — pointing them to the gene alpha-actinin-3 (ACTN3).

The scientists then started studying a variation in ACTN3, ultimately discovering it is absent in roughly 1.5 billion people. This is likely due to a mutation in the gene that codes for it.

Why ACTN3 is important — A muscle comprises of multiple fibers resembling long steel cables. Proteins called actin and myosin make it possible for these muscle fibers to contract.

Actin and myosin proteins are arranged tightly on top of each other as elongated filaments. When a muscle contracts, the myosin protein latches onto actin and pulls it at the end of the fiber. That eventually causes the muscle to move.

The ACTN3 gene — also known as the “speed gene”— plays an important role in the actin and myosin contraction of muscle fibers. Professional sprinters possess the ACTN3 gene. Scientists say it is associated with speed and power, Brazaitis says.

“There are two types of muscle fibers — slow-twitch and fast-twitch. While slow-twitch fibers conserve energy, fast-twitch fibers consume more,” co-author Håkan Westerblad, a professor of cellular muscle physiology at the Karolinska Institute in Sweden, tells Inverse.

Alpha-actinin-3 protein is expressed only in explosive or fast-twitch muscle fibers and not in slow-twitch fibers, he adds.

What’s new — This study suggests people with alpha-actinin-3 deficiency, or the loss-of-function ACTN3 gene variant, have a better cold tolerance thanks to their slow-twitch muscle fibers.

“Slow-twitch fibers generate heat effectively. People with an actinin-3 deficiency do not shiver during cold exposure. Instead, they save energy by increasing their muscle tone,” Westerblad says.

For their experiments, the researchers recruited 42 male residents from Kaunas, a city in southern Lithuania with either the functioning ACTN3 or the gene variant. They were between the ages of 18 to 40 and led a moderately active lifestyle of 2 hours of exercising a week.

"People with an actinin-3 deficiency do not shiver during cold exposure."

In an indoor pool, the researchers immersed the participants in 14 degrees Celsius water for 20-minute periods with 10-minute breaks in room temperature air. The researchers continued exposing the participants to cold water for 120 minutes until their rectal temperature reached 35.5 degrees Celsius.

Only 30 percent of the participants with the functioning ACTN3 gene could maintain their body temperature above 35.5 degrees Celsius, while 69 percent of those with the gene variant could do so after cold-water exposure.

In another experiment, 12-week old female mice with the gene variant were exposed to cold water for 5 hours. The researchers observed mice with alpha-actinin-3 deficiency did not experience an increase in cold-induced brown adipose tissue. This tissue typically generates heat in infants and hibernating mammals.

“Our study found that muscles are a very important heat source. They can produce heat by several mechanisms. Heat generation in brown fat tissue is of much less importance,” Westerblad says.

When muscles are activated, there is a release of calcium inside the slow-twitch muscle fibers.

“That calcium then has to be pumped back into the stores in muscle fibers from where it goes into the cytoplasm inside the cell, and then back into the store,” Westerblad explains. “This mechanism generates more heat in alpha-actinin-3 deficient people.”

Why it matters — While evolution over thousands of years has ensured that alpha-actinin-3 deficient people can stay warm and maintain their body temperature by using little energy, that also means their muscles consume less energy.

“It is our hypothesis or assumption at this point that people with the gene variant who consume more calories and are physically inactive could be at a higher risk of obesity, type-2 diabetes, and other metabolic disorders,” says Brazaitis.

The results, in turn, suggest there might be some potential drawbacks for people with the loss-of-function ACTN3 variant. Westerblad also warns of a higher risk of falling in older people.

This is because people with the variant gene also have lesser high-twitch muscle fibers (that handle explosive movements) as compared to those with functioning ACTN3.

What’s next — The team says these findings can help in studying inherited diseases like muscular dystrophy that damage and weaken muscles over a period. A 2017 study published in the journal Nature Communications suggests alpha-actinin-3 deficiency reduces muscle strength in patients with muscular dystrophy but improves their disease progression.

“It could be useful to further study whether an alpha-actinin-3 deficiency in muscular dystrophy could cause bigger problems or if it might offer protection for people who are missing two kinds of actin proteins — alpha-actinin-2 and alpha-actinin-3,” Westerblad says.

Summary: The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X). The prevalence of the 577X allele increased as modern humans moved to colder climates, suggesting a link between α-actinin-3 deficiency and improved cold tolerance. Here, we show that humans lacking α-actinin-3 (XX) are superior in maintaining core body temperature during cold-water immersion due to changes in skeletal muscle thermogenesis. Muscles of XX individuals displayed a shift toward more slow-twitch isoforms of myosin heavy chain (MyHC) and sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal muscle activation resulting in increased tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations in brown adipose tissue (BAT) properties that could explain the improved cold tolerance in XX individuals. Thus, this study provides a mechanism for the positive selection of the ACTN3 X-allele in cold climates and supports a key thermogenic role of skeletal muscle during cold exposure in humans.