Department of Physiology and Cellular Biophysics, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Cell Metab. 2011 Aug 3;14(2):196-207. doi: 10.1016/j.cmet.2011.05.014.
Age-related loss of muscle mass and force (sarcopenia) contributes to disability and increased mortality. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum calcium release channel required for muscle contraction. RyR1 from aged (24 months) rodents was oxidized, cysteine-nitrosylated, and depleted of the channel-stabilizing subunit calstabin1, compared to RyR1 from younger (3-6 months) adults. This RyR1 channel complex remodeling resulted in "leaky" channels with increased open probability, leading to intracellular calcium leak in skeletal muscle. Similarly, 6-month-old mice harboring leaky RyR1-S2844D mutant channels exhibited skeletal muscle defects comparable to 24-month-old wild-type mice. Treating aged mice with S107 stabilized binding of calstabin1 to RyR1, reduced intracellular calcium leak, decreased reactive oxygen species (ROS), and enhanced tetanic Ca(2+) release, muscle-specific force, and exercise capacity. Taken together, these data indicate that leaky RyR1 contributes to age-related loss of muscle function.
年龄相关的肌肉质量和力量损失（肌肉减少症）导致残疾和死亡率增加。Ryanodine 受体 1（RyR1）是骨骼肌肌浆网钙释放通道，是肌肉收缩所必需的。与年轻（3-6 个月）成年人的 RyR1 相比，来自老年（24 个月）啮齿动物的 RyR1 发生了氧化、半胱氨酸亚硝化为稳定通道的辅助亚单位 calstabin1 耗竭。这种 RyR1 通道复合物重构导致“渗漏”通道的开放概率增加，导致骨骼肌内钙泄漏。同样，携带 RyR1-S2844D 突变通道的 6 个月大的小鼠表现出与 24 个月大的野生型小鼠相当的骨骼肌缺陷。用 S107 处理老年小鼠可稳定 calstabin1 与 RyR1 的结合，减少细胞内钙泄漏，减少活性氧（ROS），增强强直性 Ca（2+）释放、肌肉特异性力和运动能力。综上所述，这些数据表明渗漏的 RyR1 导致与年龄相关的肌肉功能丧失。
