In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.

中文翻译：

---

E-syt1 抑制通过改善骨骼肌线粒体功能减轻肌肉减少性肥胖


在衰老和代谢性疾病中，肌肉减少性肥胖 （SO） 与肌内脂肪组织 （IMAT） 相关。利用生物信息学分析，我们在 SO 中发现了一种潜在的靶蛋白扩展突触结合蛋白 1 （E-syt1）。为了研究 E-syt1 在肌肉代谢中的调节作用，我们通过 E-syt1 对肌肉生理学的功能丧失和获得进行了体内和体外实验。当 E-syt1 在体外过表达时，成肌细胞增殖、分化、线粒体呼吸、生物发生和线粒体动力学受损，E-syt1 的沉默减轻了这些障碍。此外，E-syt1 的过表达抑制了线粒体自噬通量。从机制上讲，E-syt1 过表达导致线粒体钙过载和线粒体 ROS 爆发，抑制线粒体与溶酶体的融合，并阻碍溶酶体的酸化。动物实验表明，抑制 E-syt1 可增加 OVX 小鼠耐力运动能力、肌肉质量、线粒体功能和肌肉纤维的氧化能力。这些发现确立了 E-syt1 是 SO 骨骼肌代谢紊乱发病机制的新贡献者。因此，靶向 E-syt1 诱导的功能障碍可能是减弱 SO 的可行策略。