Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA.
Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA; Oklahoma City VA Medical Center, Oklahoma City, OK 73104, USA.
Redox Biol. 2019 Jan;20:68-74. doi: 10.1016/j.redox.2018.09.018. Epub 2018 Sep 27.
Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca ATPase (SERCA) with CDN1163, a novel small molecule allosteric SERCA activator, ameliorates the muscle impairment in the CuZnSOD deficient (Sod1) mouse model of oxidative stress. Sod1 mice are characterized by reduced SERCA activity, muscle weakness and atrophy, increased oxidative stress and mitochondrial dysfunction. Seven weeks of CDN1163 treatment completely restored SERCA activity and reversed the 23% reduction in gastrocnemius mass and 22% reduction in specific force in untreated Sod1 versus wild type mice. These changes were accompanied by restoration of autophagy protein markers to the levels found in wild-type mice. CDN1163 also reversed the increase in mitochondrial ROS generation and oxidative damage in muscle tissue from Sod1 mice. Taken together our findings suggest that the pharmacological restoration of SERCA is a promising therapeutic approach to counter oxidative stress-associated muscle impairment.
由于氧化应激导致肌肉无力和萎缩的分子靶点一直难以捉摸。在这里，我们表明，使用新型小分子别构肌浆网 Ca ATP 酶（SERCA）激活剂 CDN1163 激活 SERCA，可以改善 CuZnSOD 缺陷（Sod1）氧化应激小鼠模型中的肌肉损伤。Sod1 小鼠的特点是 SERCA 活性降低、肌肉无力和萎缩、氧化应激和线粒体功能障碍增加。7 周的 CDN1163 治疗完全恢复了 SERCA 活性，并逆转了未经治疗的 Sod1 与野生型小鼠相比，腓肠肌质量减少 23%和比特定力减少 22%的情况。这些变化伴随着自噬蛋白标志物恢复到野生型小鼠的水平。CDN1163 还逆转了 Sod1 小鼠肌肉组织中线粒体 ROS 生成和氧化损伤的增加。总之，我们的研究结果表明，SERCA 的药理学恢复是一种有前途的治疗方法，可对抗与氧化应激相关的肌肉损伤。
