ArticleAmerican journal of human genetics2021
Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation.
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 50 citations in OpenAlex.
- Evolution of Adaptive Non-Shivering Thermogenesis in Mammals.Physiology (Bethesda, Md.) · 2026Review
- Metabolic Health and Fitness Do Not Differ Substantially Between Overweight Adults With and Without α-Actinin-3 Deficiency.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- Skeletal Fiber Type in Muscle Pain and Dysfunction.Biomedicines · 2026Review
- Body Temperature Regulation in the Rat by Muscle Tone.Acta physiologica (Oxford, England) · 2026Article
- Polymorphic pseudogenes in the human genome - a comprehensive assessment.Human genetics · 2024Article
- Adaptive Induction of Nonshivering Thermogenesis in Muscle Rather Than Brown Fat Could Counteract Obesity.Physiological research · 2024Review
- Article
- Review
- Absence of the Z-disc protein α-actinin-3 impairs the mechanical stability of Actn3KO mouse fast-twitch muscle fibres without altering their contractile properties or twitch kinetics.Skeletal muscle · 2022Article
- Response to Mörseburg et al.American journal of human genetics · 2022Article
- Response to Wyckelsma et al.: Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation.American journal of human genetics · 2022Article
- Loss of α-actinin-3 confers protection from eccentric contraction damage in fast-twitch EDL muscles from aged mdx dystrophic mice by reducing pathological fibre branching.Human molecular genetics · 2022Article
- Functional Impact of Post-exercise Cooling and Heating on Recovery and Training Adaptations: Application to Resistance, Endurance, and Sprint Exercise.Sports medicine - open · 2022Review
- Effect of the ACTN-3 gene polymorphism on functional fitness and executive function of elderly.Frontiers in aging neuroscience · 2022Article
- Human vulnerability and variability in the cold: Establishing individual risks for cold weather injuries.Temperature (Austin, Tex.) · 2022Review
- A Positively Selected MAGEE2 LoF Allele Is Associated with Sexual Dimorphism in Human Brain Size and Shows Similar Phenotypes in Magee2 Null Mice.Molecular biology and evolution · 2021Article
- Population Genetic Polymorphism of Skeletal Muscle Strength Related Genes in Five Ethnic Minorities in North China.Frontiers in genetics · 2021Article
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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