Why is α-actinin-3 deficiency so common in the general population?: The evolution of athletic performance
Why is α-actinin-3 deficiency so common in the general population?: The evolution of athletic performance
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DOI：
10.1375/twin.11.4.384
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发表时间：
2008-08-01
影响因子：
0.9
通讯作者：
North, Kathryn
中科院分区：
文献类型：
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作者：
North, Kathryn
人ACTN 3基因编码蛋白α-辅肌动蛋白-3，其是快速骨骼肌纤维中收缩装置的组分。1999年，我们发现了一种常见的ACTN 3多态性（R577 X），导致全球超过10亿人缺乏α-辅肌动蛋白-3，尽管ACTN 3基因在人类进化过程中高度保守。在2003年，我们证明了ACTN 3基因型影响精英运动员的表现，ACTN 3基因型和骨骼肌性能之间的关联已被复制在运动员和非运动员队列。我们还研究了R577 X等位基因在人类进化过程中的进化，并证明了无效W等位基因在欧洲人和亚洲人中经历了强烈的，最近的正选择。我们已经开发了一种Actn 3基因敲除小鼠模型，该模型复制了人类α-辅肌动蛋白-3缺乏症，并且已经深入了解了α-辅肌动蛋白-3在调节骨骼肌代谢、纤维大小、肌肉质量和收缩特性中的作用。特别是，缺乏α-辅肌动蛋白-3的小鼠肌肉更有效地利用能量，快速纤维显示出缓慢氧化纤维的代谢和收缩特性。虽然这有利于耐力活动，但代价是肌肉不能产生在短跑中表现出色所需的快速收缩。我们认为，向更有效的有氧肌肉代谢与α-辅肌动蛋白-3缺乏相关的转变也是577 X等位基因的适应性益处的基础。我们未来的研究将集中在ACTN 3基因型对运动和衰老反应的影响，以及肌肉疾病表型的发生和严重程度。
The human ACTN3 gene encodes the protein alpha-actinin-3, a component of the contractile apparatus in fast skeletal muscle fibers. In 1999, we identified a common polymorphism in ACTN3 (R577X) that results in absence of alpha-actinin-3 in more than one billion people worldwide, despite the ACTN3 gene being highly conserved during human evolution. In 2003, we demonstrated that ACTN3 genotype influences elite athletic performance, and the association between ACTN3 genotype and skeletal muscle performance has since been replicated in athletes and non-athlete cohorts. We have also studied the evolution of the R577X allele during human evolution and demonstrated that the null W allele has undergone strong, recent positive selection in Europeans and Asian populations. We have developed an Actn3 knockout mouse model that replicates alpha-actinin-3 deficiency in humans and has already provided insight into the role of alpha-actinin-3 in the regulation of skeletal muscle metabolism, fibre size, muscle mass and contractile properties. In particular, mouse muscle lacking alpha-actinin-3 uses energy more efficiently, with the fast fibers displaying metabolic and contractile properties of slow oxidative fibers. While this favors endurance activities, the trade off is that the muscle cannot generate the rapid contractions needed to excel in sprinting. We propose that the shift towards more efficient aerobic muscle metabolism associated with alpha-actinin-3 deficiency also underlies the adaptive benefit of the 577X allele. Our future studies will focus on the effect of ACTN3 genotype on response to exercise and ageing, and the onset and severity of muscle disease phenotype.