A genetic variant that affects skeletal muscle function may have protected people from lower temperatures as they migrated from Africa to Europe more than 50,000 years ago, suggests a study that appeared Feb. 17 in American Journal of Human Genetics. It is known that the variant loss of function (LOF) of the ACTN3 gene results in the loss of a skeletal muscle protein called α-actinin-3 and that it is becoming more prevalent as modern humans have moved to colder environments. Researchers now show that a-actinin-3 deficiency improves cold tolerance in humans by increasing muscle tone.
“Our research shows improved cold tolerance in people who lack α-actinin-3, which would represent an evolutionary advantage of survival if they moved to a colder climate,” says co-senior study author Håkan Westerblad of the Karolinska Institutet. “Our research also emphasizes the great importance of skeletal muscle as a heat generator in humans.”
Approximately 1.5 billion people worldwide carry the ACTN3 LOF variant and therefore lack α-actinin-3. Although the lack of this protein is not related to muscle diseases, it reduces performance during strength and sprint activities. As the LOF variant became more abundant as people moved to colder climates, Westerblad and co-senior study author Marius Brazaitis of the Lithuanian Sports University doubted it could play a role in improving cold tolerance.
To test this idea, the researchers immersed 42 healthy adult men aged 18 to 40 with a LOF variant or functional ACTN3 in 14 ° C water for 20-minute periods, interspersed with ten-minute breaks in room temperature air. Exposure to cold water was continued until the rectal temperature reached 35.5 ° C, or a total of 120 minutes (170 minutes, including breaks). While 69% of subjects with the LOF variant were able to maintain a body temperature above 35.5 ° C for complete exposure to cold water, only 30% of participants with functional ACTN3 were able to do so. On average, loss of α-actinin-3 resulted in half the rate of temperature drop in the rectum and calf muscle.
LOF carriers also showed a shift toward slower muscle fibers, resulting in increased muscle tone rather than open tremor during cold water immersion. In contrast, individuals with functional ACTN3 had more muscle fibers twitching rapidly, doubling the rate of high-intensity bursts. Superior cold resistance of LOF carriers is not accompanied by an increase in energy consumption, suggesting that continuous activation of low-intensity slow-muscle fibers is an energy-efficient way to generate heat. Additional results in mice showed that α-actinin-3 deficiency did not increase cold-induced brown adipose tissue, which generates heat in hibernating mammals and human infants.
For now, it remains uncertain whether the loss of α-actinin-3 affects brown adipose tissue or tolerance to colds in human newborns, whose survival would be an important factor during human migration to a colder environment. Although the LOF variant can increase muscle fibers that twitch slowly at birth, it is possible for this shift to occur later in life. Moreover, it is not clear whether α-actinin-3 deficiency affects heat tolerance or reactions to different types of athletic training.
“While there are many avenues for future investigations, our results increase our understanding of the evolutionary aspects of human migration,” says Brazaitis. “While energy-efficient heat generation in people who lack α-actinin-3 would be an advantage when moving to a colder climate, it could actually be a disadvantage in modern societies, where housing and clothing make cold protection less important and where we basically have unrestricted access to food, so energy efficiency can be a problem and result in obesity, type 2 diabetes and other metabolic disorders. “
This work was supported by the Swedish Medical Research Council, the Swedish Sports Science Research Council, the Lithuanian Research Council, the Swedish Medical Research Society, the Jeansson Foundation, the Swedish Heart-Lung Foundation and the Australian National Health and Medicine Research Council. VML is the founder, CEO and shareholder of HepaPredict AB. In addition, VML reveals consulting work for EnginZyme AB.
American Journal of Human Genetics, Wyckelsma et al: “Loss of α-actinin-3 during human evolution provides superior resistance to cold and heat generation in muscles” https://www.cell.com/ajhg/fulltext/S0002-9297(21)00013-6
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