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

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journal contribution
posted on 03.05.2021, 00:04 by Victoria Wyckelsma, T Venckunas, PJ Houweling, M Schlittler, VM Lauschke, CF Tiong, HD Wood, N Ivarsson, H Paulauskas, N Eimantas, DC Andersson, KN North, M Brazaitis, H 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 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.

History

Publication Date

04/03/2021

Journal

American Journal of Human Genetics

Volume

108

Issue

3

Pagination

(p. 446-457)

Publisher

Elsevier BV

ISSN

0002-9297

Rights Statement

The Authors reserves all moral rights over the deposited text and must be credited if any re-use occurs.