Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness.
Restoration of SERCA ATPase prevents oxidative stress-related muscle atrophy and weakness.
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DOI：
10.1016/j.redox.2018.09.018
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Van Remmen H
中科院分区：
文献类型：
--
作者：
Qaisar R;Bhaskaran S;Ranjit R;Sataranatarajan K;Premkumar P;Huseman K;Van Remmen H
减轻氧化应激引起的肌肉无力和萎缩的分子靶点一直难以捉摸。在这里，我们证明了肌浆网(SR)钙ATPase(SERCA)被新型小分子变构SERCA激活剂CDN1163激活，改善了CuZnSOD缺乏(SOD-/-)小鼠氧化应激模型的肌肉损伤。SOD1-/-小鼠的特点是SERCA活性降低，肌肉无力和萎缩，氧化应激增加和线粒体功能障碍。7周的CDN1163治疗完全恢复了SERCA的活性，并逆转了未经治疗的SOD1-/-小鼠腓肠肌质量减少23%和比力减少22%的情况。伴随着这些变化的是自噬蛋白标记物恢复到野生型小鼠的水平。CDN1163还逆转了SOD1-/-小鼠肌肉组织线粒体ROS生成和氧化损伤的增加。综上所述，我们的研究结果表明，SERCA的药理学恢复是对抗氧化应激相关肌肉损伤的一种有前途的治疗方法。氧化应激与SOD1-/-小鼠SERCA功能障碍和肌肉缺陷有关。CDN1163可恢复SOD1-/-小鼠的SERCA，防止氧化应激和肌肉缺陷。CDN1163为治疗与氧化应激相关的肌肉缺陷提供了一种有前途的治疗方法。
Molecular targets to reduce muscle weakness and atrophy due to oxidative stress have been elusive. Here we show that activation of Sarcoplasmic Reticulum (SR) Ca2+ 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. Oxidative stress is related to SERCA dysfunction and muscle defect in Sod1-/- mice. CDN1163 restores SERCA and prevents oxidative stress and muscle defect in Sod1-/- mice. CDN1163 offers a promising therapy for muscle defect related to oxidative stress.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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10.1152/ajpregu.00767.2006
发表时间：
2007-09-01
影响因子：
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