Journal article
Loss of alpha-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, Hakan Westerblad
AMERICAN JOURNAL OF HUMAN GENETICS | CELL PRESS | Published : 2021
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 neurona..
View full abstractGrants
Awarded by Swedish Medical Research Council
Awarded by Swedish Research Council for Sport Science
Awarded by Research Council of Lithuania
Awarded by Swedish Society for Medical Research (SSMF)
Awarded by Jeansson's Foundation
Awarded by Swedish Heart-Lung Foundation
Awarded by Australian National Health and Medical Research Council (NHMRC)
Funding Acknowledgements
This study was funded by grants to H.W. from the Swedish Medical Research Council (2018-02576) and the Swedish Research Council for Sport Science (P2019-060); to M.B. from the Research Council of Lithuania (S-02/SMT12P-014 and 01/SMT13P-176); to D.C.A. from the Swedish Society for Medical Research (SSMF, S16-0159), the Jeansson's Foundation (JS2018-0131), and the Swedish Heart-Lung Foundation (20180637, 2016074); and to K.N.N. from the Australian National Health and Medical Research Council (NHMRC, APP1130215). We thank Monika Kisieliute and Andreius Subocius for their assistance in genotyping and collection of human muscle biopsies. We also thank Sophie Agius and Alison Burns for their contribution to maintaining the Actn3 KO mouse colony.