People With Muscle Protein Gene Variant Found to Tolerate Cold Better

A new study suggests that a gene variant affecting skeletal muscle function may have protected humans against lower temperatures as they migrated from Africa to Europe more than 50,000 years ago.

Steve Kent skis through Times Square during a snowstorm, Monday, Feb. 1, 2021, in the Manhattan borough of New York. (AP Photo/John Minchillo)

(CN) — As fierce winter storms and low temperatures pummel much of the U.S., people with lower levels of a specific skeletal muscle protein may fare better than most in the cold.

A study published Wednesday in the American Journal of Human Genetics finds that the loss-of-function variant of the ACTN3 gene drops the levels of α-actinin-3, which improves cold tolerance in humans by increasing muscle tone.

Researchers immersed 42 healthy male adults aged 18 to 40 with either the loss-of-function variant or functioning ACTN3 in 57-degree water for 20-minute periods, interspersed by 10-minute pauses in air at room temperature. Cold-water exposure was continued until the subjects’ body temperature reached about 96 degrees or for a total of 120 minutes. They found that 69% of subjects with the loss-of-function variant maintained their body temperature above 96°F for the full cold-water exposure time, as opposed to only 30% of participants with functioning ACTN3.

On average, those with low levels of α-actinin-3 suffered half the rate of temperature decline of those with higher levels of the skeletal muscle protein.

Approximately 1.5 billion people worldwide carry the ACTN3 loss-of-function variant and therefore lack α-actinin-3. Because the loss-of-function variant became more abundant as humans moved to colder climates, co-senior study authors Håkan Westerblad of the Karolinska Institutet and Marius Brazaitis of Lithuanian Sports University suspected that it might play a role in improving cold tolerance.

“Our study shows an improved cold tolerance in people lacking α-actinin-3, which would have been an evolutionary survival advantage when moving to colder climates,” says Westerblad. “Our study also highlights the great importance of skeletal muscle as a heat generator in humans.”

Study participants with lower levels of α-actinin-3 had more slow-twitch muscle fibers, resulting in an increase in muscle tone rather than overt shivering during cold-water immersion. By contrast, individuals with higher levels of the protein had more fast-twitch muscle fibers, which meant more shivering. Additional results in mice showed that α-actinin-3 deficiency does not increase cold-induced brown fat tissue, which generates heat in hibernating mammals and human infants.

For now, it remains uncertain whether the loss of α-actinin-3 affects brown fat tissue or cold tolerance of human infants, whose survival would have been an important factor during the human migration to colder environments. While the loss-of-function variant may increase slow-twitch muscle fibers at birth, it is possible that this shift occurs later in life. Moreover, it’s not clear whether α-actinin-3 deficiency affects heat tolerance or responses to different types of athletic training.

“Although there are many avenues for future investigation, our results increase our understanding of evolutionary aspects of human migration,” Brazaitis says. “While the energetically efficient heat generation in people lacking α-actinin-3 would have been an advantage when moving to colder climates, it might actually be a disadvantage in modern societies, where housing and clothing make cold protection less important, and where we basically have unlimited access to food, such that energy efficiency can impose a problem and result in obesity, type 2-diabetes, and other metabolic disorders.”

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