TY - JOUR T1 - Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation JF - bioRxiv DO - 10.1101/2020.10.03.323964 SP - 2020.10.03.323964 AU - VL Wyckelsma AU - T Venckunas AU - PJ Houweling AU - M Schlittler AU - VM Lauschke AU - CF Tiong AU - H Wood AU - N Ivarsson AU - H Paulauskas AU - N Eimantas AU - DC Andersson AU - KN North AU - M Brazaitis AU - H Westerblad Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/10/03/2020.10.03.323964.abstract N2 - The fast skeletal muscle protein α-actinin-3 is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in the ACTN3 gene (R577X) 1. 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 1,2. 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 towards 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 3,4. 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 clear 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.Competing Interest StatementVolker M Lauschke is founder, CEO, and shareholder of HepaPredict AB. In addition, V.M.L. discloses consultancy work for EnginZyme AB. ER -