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人类进化过程中 α-辅肌动蛋白-3 的丧失赋予了更优越的抗寒能力和肌肉产热能力。

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

机构信息

Department of Physiology and Pharmacology, Biomedicum, Karolinska Institutet, 171 77 Stockholm, Sweden.

Institute of Sport Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania.

出版信息

Am J Hum Genet. 2021 Mar 4;108(3):446-457. doi: 10.1016/j.ajhg.2021.01.013. Epub 2021 Feb 17.

DOI:10.1016/j.ajhg.2021.01.013
PMID:33600773
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8008486/
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 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.

摘要

由于 ACTN3（R577X）中的无义多态性导致纯合，全世界有 15 亿人缺乏表达于快肌纤维的蛋白α-辅肌动蛋白-3。随着现代人迁移到更寒冷的气候中，577X 等位基因的流行率增加，这表明α-辅肌动蛋白-3缺乏与提高耐寒性之间存在联系。在这里，我们表明由于骨骼肌产热的变化，缺乏α-辅肌动蛋白-3（XX）的人类在冷水浸泡期间更能维持核心体温。XX 个体的肌肉表现出向肌球蛋白重链（MyHC）和肌浆网（SR）蛋白的慢肌同工型的转变，伴随着神经元肌肉激活的改变，导致张力增加而不是明显的颤抖。对 Actn3 敲除小鼠的实验表明，棕色脂肪组织（BAT）的特性没有改变，这不能解释 XX 个体耐寒性的提高。因此，这项研究为 ACTN3 X 等位基因在寒冷气候中的正选择提供了一种机制，并支持了人类在寒冷暴露期间骨骼肌的关键产热作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/77bbd1ea2c09/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/b7d11b60b88f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/18ac0e3e984a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/893da2b4b489/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/45b9a8baa092/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/77bbd1ea2c09/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/b7d11b60b88f/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/18ac0e3e984a/gr2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/893da2b4b489/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/45b9a8baa092/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/f141/8008486/77bbd1ea2c09/gr5.jpg

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