Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation

• DOI: 10.1016/j.ajhg.2021.01.013
• Publication Date: 2021-02-17T20:51:28Z
• Authors: Victoria L. Wycke...; Tomas Venckunas; Peter J. Houweling; Maja Schlittler; Volker M. Lauschke; Chrystal F. Tiong; Harrison D. Wood; Niklas Ivarsson; Henrikas Paulauskas; Nerijus Eimantas; Daniel C. Andersson; Kathryn N. North; Marius Brazaitis; Håkan Westerblad
• Keywords: Resilience; Cold chain

The protein α-actinin-3 expressed in fast-twitch skeletal muscle fiber is absent 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism ACTN3 (R577X). prevalence of the 577X allele increased as modern humans moved colder climates, suggesting link between deficiency and improved cold tolerance. Here, we show that lacking (XX) are superior maintaining core body temperature during cold-water immersion changes thermogenesis. Muscles XX individuals displayed shift toward more slow-twitch isoforms myosin heavy chain (MyHC) sarcoplasmic reticulum (SR) proteins, accompanied by altered neuronal activation resulting tone rather than overt shivering. Experiments on Actn3 knockout mice showed no alterations brown adipose tissue (BAT) properties could explain tolerance individuals. Thus, this study provides mechanism positive selection X-allele climates supports key thermogenic role exposure humans.