Seto Jane T, Roeszler Kelly N, Meehan Lyra R, Wood Harrison D, Tiong Chrystal, Bek Lucinda, Lee Siaw F, Shah Manan, Quinlan Kate G R, Gregorevic Paul, Houweling Peter J, North Kathryn N
Murdoch Children's Research Institute, The Royal Children's Hospital, Melbourne, VIC, Australia.
Department of Paediatrics, University of Melbourne, The Royal Children's Hospital, Melbourne, VIC, Australia.
Sci Adv. 2021 Jul 2;7(27). doi: 10.1126/sciadv.abg0088. Print 2021 Jul.
Homozygosity for the common null polymorphism ( 577X) results in α-actinin-3 deficiency in ~20% of humans worldwide and is linked to reduced sprint and power performance in both elite athletes and the general population. α-Actinin-3 deficiency is also associated with reduced muscle mass, increased risk of sarcopenia, and altered muscle wasting response induced by denervation and immobilization. Here, we show that α-actinin-3 plays a key role in the regulation of protein synthesis and breakdown signaling in skeletal muscle and influences muscle mass from early postnatal development. We also show that α-actinin-3 deficiency reduces the atrophic and anti-inflammatory response to the glucocorticoid dexamethasone in muscle and protects against dexamethasone-induced muscle wasting in female but not male mice. The effects of α-actinin-3 deficiency on muscle mass regulation and response to muscle wasting provide an additional mechanistic explanation for the positive selection of the 577X allele in recent human history.
常见的无效多态性（577X）的纯合性导致全世界约20%的人缺乏α-辅肌动蛋白-3，并且与精英运动员和普通人群的短跑及力量表现降低有关。α-辅肌动蛋白-3缺乏还与肌肉量减少、患肌肉减少症的风险增加以及去神经支配和固定化诱导的肌肉萎缩反应改变有关。在此，我们表明α-辅肌动蛋白-3在骨骼肌蛋白质合成和分解信号的调节中起关键作用，并从出生后早期发育阶段就影响肌肉量。我们还表明，α-辅肌动蛋白-3缺乏会降低肌肉对糖皮质激素地塞米松的萎缩和抗炎反应，并在雌性而非雄性小鼠中预防地塞米松诱导的肌肉萎缩。α-辅肌动蛋白-3缺乏对肌肉量调节和肌肉萎缩反应的影响为近期人类历史中577X等位基因的正向选择提供了额外的机制解释。
