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



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..

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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.