J Clin Invest. 2013 Oct;123(10):4255-63. doi: 10.1172/JCI67691. Epub 2013 Sep 16.
α-Actinin-3 deficiency occurs in approximately 16% of the global population due to homozygosity for a common nonsense polymorphism in the ACTN3 gene. Loss of α-actinin-3 is associated with reduced power and enhanced endurance capacity in elite athletes and nonathletes due to "slowing" of the metabolic and physiological properties of fast fibers. Here, we have shown that α-actinin-3 deficiency results in increased calcineurin activity in mouse and human skeletal muscle and enhanced adaptive response to endurance training. α-Actinin-2, which is differentially expressed in α-actinin-3-deficient muscle, has higher binding affinity for calsarcin-2, a key inhibitor of calcineurin activation. We have further demonstrated that α-actinin-2 competes with calcineurin for binding to calsarcin-2, resulting in enhanced calcineurin signaling and reprogramming of the metabolic phenotype of fast muscle fibers. Our data provide a mechanistic explanation for the effects of the ACTN3 genotype on skeletal muscle performance in elite athletes and on adaptation to changing physical demands in the general population. In addition, we have demonstrated that the sarcomeric α-actinins play a role in the regulation of calcineurin signaling.
由于 ACTN3 基因中的一种常见无义多态性的纯合性，全球约有 16%的人群存在α-辅肌动蛋白-3 缺乏。由于“减缓”快肌纤维的代谢和生理特性，α-辅肌动蛋白-3 的缺失与优秀运动员和非运动员的力量减弱和耐力增强能力有关。在这里，我们已经表明，α-辅肌动蛋白-3 缺乏会导致小鼠和人类骨骼肌中的钙调神经磷酸酶活性增加，并增强对耐力训练的适应性反应。α-辅肌动蛋白-2 在α-辅肌动蛋白-3 缺乏的肌肉中表达不同，与钙调神经磷酸酶激活的关键抑制剂 calsarcin-2 的结合亲和力更高。我们进一步证明，α-辅肌动蛋白-2 与钙调神经磷酸酶竞争与 calsarcin-2 的结合，导致钙调神经磷酸酶信号增强和快肌纤维代谢表型的重新编程。我们的数据为 ACTN3 基因型对优秀运动员的骨骼肌性能以及对普通人群中不断变化的身体需求的适应的影响提供了机制解释。此外，我们已经证明，肌节 α-辅肌动蛋白在钙调神经磷酸酶信号转导的调节中起作用。
