Summary: New research shows that lacking the muscle protein α-actinin-3 improves human cold tolerance by increasing sustained muscle tone. An estimated 1.5 billion people worldwide carry the ACTN3 loss-of-function variant that causes this deficiency.
Source: Cell Press
A common genetic variant that affects skeletal muscle physiology may have helped early humans cope with colder climates as they migrated out of Africa. In a study published in the American Journal of Human Genetics, researchers report that a loss-of-function (LOF) variant in the ACTN3 gene—resulting in absence of the muscle protein α-actinin-3—improves cold tolerance in humans by promoting increased muscle tone and shifting muscle composition toward more slow-twitch fibers.
Co-senior author Håkan Westerblad of the Karolinska Institutet explains: “Our findings show that people who lack α-actinin-3 tolerate cold better, which likely provided an evolutionary benefit when humans moved into cooler environments. The results also emphasize the central role of skeletal muscle as a generator of heat in humans.”
About 1.5 billion people worldwide are homozygous for the ACTN3 R577X polymorphism and therefore do not produce functional α-actinin-3. This deficiency is not linked to a muscle disease but is known to reduce performance in high-power and sprint activities. Because the R577X allele increased in frequency as modern humans moved into higher latitudes, the authors investigated whether α-actinin-3 deficiency could offer an advantage in cold environments.
To test this hypothesis, the team recruited 42 healthy men aged 18 to 40 who either carried the LOF ACTN3 genotype (XX) or had a functioning ACTN3 gene. Participants underwent repeated cold-water immersion at 14 °C: 20-minute immersion periods separated by 10-minute breaks in room-temperature air. The protocol continued until participants’ rectal temperature reached 35.5 °C or until a total immersion time of 120 minutes (170 minutes including breaks) was reached.
Results showed a clear difference in resilience to cold exposure. Among individuals lacking α-actinin-3, 69% maintained core body temperature above 35.5 °C for the full exposure period. By contrast, only 30% of participants with a functional ACTN3 gene completed the protocol without their rectal temperature dropping below 35.5 °C. On average, people without α-actinin-3 experienced roughly half the rate of core and calf muscle temperature decline compared with those who expressed the protein.
Muscle analyses revealed that α-actinin-3 deficient individuals exhibited a shift in muscle composition toward slow-twitch (type I) fiber characteristics and corresponding changes in sarcoplasmic reticulum proteins and myosin heavy chain isoforms. This shift correlated with altered neuronal activation patterns: instead of pronounced shivering, LOF carriers displayed increased continuous low-level muscle activation—elevated muscle tone—which produced heat more steadily. Conversely, participants with functional ACTN3 had more fast-twitch fibers and showed a higher rate of intermittent, high-intensity burst activity during cold exposure.
Importantly, the improved cold resistance in LOF carriers did not come with an increase in measured energy expenditure, suggesting that sustained activation of slow-twitch fibers is an energetically efficient method of thermogenesis. Complementary experiments in Actn3 knockout mice showed no enhancement of brown adipose tissue (BAT) activity that would explain the human phenotype, supporting the conclusion that skeletal muscle thermogenesis—rather than BAT—accounts for the observed advantage.
Several questions remain open. It is not yet known whether α-actinin-3 deficiency influences thermoregulation in infants—whose survival in cold climates would have been crucial during human migration—or whether the shift toward slow-twitch muscle fibers is present at birth or develops later in life. The study also does not determine whether α-actinin-3 deficiency affects heat tolerance in warm environments or modifies responses to different training regimens.
Co-senior author Marius Brazaitis of Lithuanian Sports University adds: “While energetically efficient heat generation would have been beneficial during migration into colder regions, in modern societies where heating, clothing, and abundant food reduce cold stress, enhanced energy efficiency could have downsides. It may contribute to energy storage and metabolic risk in environments with unlimited calories.”
Funding: This research received support from the Swedish Medical Research Council, the Swedish Research Council for Sport Science, the Research Council of Lithuania, the Swedish Society for Medical Research, Jeansson’s foundation, the Swedish Heart-Lung Foundation, and the Australian National Health and Medical Research Council. V.M.L. is founder, CEO, and shareholder of HepaPredict AB and has disclosed consultancy work for EnginZyme AB.
About this genetics research news
Source: Cell Press
Contact: Carly Britton – Cell Press
Image: The image is in the public domain
Original Research: Open access. “Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation” by Håkan Westerblad et al., American Journal of Human Genetics
Abstract
Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation
α-Actinin-3 is a structural protein expressed primarily in fast-twitch skeletal muscle fibers. A common nonsense polymorphism in ACTN3 (R577X) results in complete absence of α-actinin-3 in approximately 1.5 billion people worldwide. The frequency of the 577X allele increased as modern humans spread into colder climates, implying a selective advantage.
This study demonstrates that individuals lacking α-actinin-3 maintain core body temperature better during acute cold-water immersion. The improved cold resilience derives from changes in skeletal muscle composition and activation: muscles favor slow-twitch isoforms of myosin heavy chain and associated sarcoplasmic reticulum proteins, and display increased sustained tone rather than intermittent shivering. Mouse experiments showed no BAT alterations to account for these effects, supporting skeletal muscle thermogenesis as the primary mechanism. These findings offer a plausible explanation for the positive selection of the ACTN3 X-allele in cold environments and highlight the importance of skeletal muscle in human thermoregulation.