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

Autor:	Wyckelsma VL; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden., Venckunas T; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania., Houweling PJ; Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia; Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC 3010, Australia., Schlittler M; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden., Lauschke VM; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden., Tiong CF; Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia; Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC 3010, Australia., Wood HD; Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia; Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC 3010, Australia., Ivarsson N; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden., Paulauskas H; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania., Eimantas N; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania., Andersson DC; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden; Heart, Vascular and Neurology Theme, Cardiology unit, Karolinska University Hospital, 171 76 Stockholm, Sweden., North KN; Murdoch Children's Research Institute, The Royal Children's Hospital Melbourne, Melbourne, VIC 3052, Australia; Department of Paediatrics, Melbourne Medical School, University of Melbourne, Melbourne, VIC 3010, Australia., Brazaitis M; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania. Electronic address: marius.brazaitis@lsu.lt., Westerblad H; Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden; Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania. Electronic address: hakan.westerblad@ki.se.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2021 Mar 04; Vol. 108 (3), pp. 446-457. Date of Electronic Publication: 2021 Feb 17.
DOI:	10.1016/j.ajhg.2021.01.013
Abstrakt:	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 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. (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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