R&D Immunology & Inflammation Therapeutic Area, Sanofi, Industriepark Hoechst, 65926, Frankfurt am Main, Germany.
R&D TMED Bioinformatics, Sanofi, Industriepark Hoechst, 65926, Frankfurt am Main, Germany.
Sci Rep. 2018 Jun 20;8(1):9408. doi: 10.1038/s41598-018-27614-8.
Mitochondrial dysfunction is increasingly recognized as a contributor to age-related muscle loss and functional impairment. Therefore, we developed a high throughput screening strategy that enabled the identification of compounds boosting mitochondrial energy production in a human skeletal muscle cell model. Screening of 7949 pure natural products revealed 22 molecules that significantly increased oxygen consumption and ATP levels in myotubes. One of the most potent compounds was the flavanone hesperetin. Hesperetin (10 µM) increased intracellular ATP by 33% and mitochondrial spare capacity by 25%. Furthermore, the compound reduced oxidative stress in primary myotubes as well as muscle tissue in vivo. In aged mice administration of hesperetin (50 mg/kg/d) completely reverted the age-related decrease of muscle fiber size and improved running performance of treated animals. These results provide a novel screening platform for the discovery of drugs that can improve skeletal muscle function in patients suffering from sarcopenia or other disorders associated with mitochondrial dysfunction.
线粒体功能障碍被认为是与年龄相关的肌肉损失和功能障碍的一个重要原因。因此，我们开发了一种高通量筛选策略，可以在人类骨骼肌细胞模型中鉴定出能促进线粒体能量产生的化合物。对 7949 种纯天然产物进行筛选，发现有 22 种分子能显著增加肌管中的耗氧量和 ATP 水平。其中最有效的化合物之一是类黄酮橙皮苷。橙皮苷（10μM）可使细胞内 ATP 增加 33%，线粒体备用容量增加 25%。此外，该化合物还能减少原代肌管和体内肌肉组织的氧化应激。在衰老小鼠中，给予橙皮苷（50mg/kg/d）可完全逆转与年龄相关的肌纤维大小减少，并改善治疗动物的跑步性能。这些结果为发现可改善患有肌肉减少症或其他与线粒体功能障碍相关疾病的患者的骨骼肌功能的药物提供了一种新的筛选平台。
