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

Victoria L Wyckelsma,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

doi:10.1016/j.ajhg.2021.01.013

Abstract

SummaryThe 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.

Highlights

Material and methodsThe sarcomeric protein a-actinin-3 resides in the Z-discs of fast-twitch skeletal muscle fibers, where it cross-links the actin filaments of adjacent sarcomeres.[1,2,3] a-actinin[3] is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X).[4]
We sought to determine whether a-actinin-3-deficient (XX) humans were better at defending their body temperature during an acute cold challenge than humans with functioning ACTN3 (RR)
Cold-water exposure of XX and RR individuals Young male XX and RR individuals (Table S1) were immersed in 14C water for 20 min periods interposed by 10 min pauses in room-temperature air; cold-water exposure was continued until the rectal temperature reached 35.5C or for a total of 120 min (170 min including the pauses)

Summary

Introduction

Material and methodsThe sarcomeric protein a-actinin-3 resides in the Z-discs of fast-twitch skeletal muscle fibers, where it cross-links the actin filaments of adjacent sarcomeres.[1,2,3] a-actinin[3] is absent in 1.5 billion people worldwide due to homozygosity for a nonsense polymorphism in ACTN3 (R577X).[4]. We sought to determine whether a-actinin-3-deficient (XX) humans were better at defending their body temperature during an acute cold challenge than humans with functioning ACTN3 (RR)

Results

Discussion

Conclusion