PT  - JOURNAL ARTICLE
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
TI  - Loss of α-actinin-3 during human evolution provides superior cold resilience and muscle heat generation
AID  - 10.1101/2020.10.03.323964
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.03.323964
4099  - http://biorxiv.org/content/early/2020/10/03/2020.10.03.323964.short
4100  - http://biorxiv.org/content/early/2020/10/03/2020.10.03.323964.full
AB  - 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.