Department of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Neurology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Sci Rep. 2022 Sep 12;12(1):15328. doi: 10.1038/s41598-022-19136-1.
Muscular dystrophies are inherited myopathic disorders characterized by progressive muscle weakness. Recently, several gene therapies have been developed; however, the treatment options are still limited. Resveratrol, an activator of SIRT1, ameliorates muscular function in muscular dystrophy patients and dystrophin-deficient mdx mice, although its mechanism is still not fully elucidated. Here, we investigated the effects of resveratrol on membrane resealing. We found that resveratrol promoted membrane repair in C2C12 cells via the activation of SIRT1. To elucidate the mechanism by which resveratrol promotes membrane resealing, we focused on the reorganization of the cytoskeleton, which occurs in the early phase of membrane repair. Treatment with resveratrol promoted actin accumulation at the injured site. We also examined the role of cortactin in membrane resealing. Cortactin accumulated at the injury site, and cortactin knockdown suppressed membrane resealing and reorganization of the cytoskeleton. Additionally, SIRT1 deacetylated cortactin and promoted the interaction between cortactin and F-actin, thus possibly enhancing the accumulation of cortactin at the injury site. Finally, we performed a membrane repair assay using single fiber myotubes from control and resveratrol-fed mice, where the oral treatment with resveratrol promoted membrane repair ex vivo. These findings suggest that resveratrol promotes membrane repair via the SIRT1/cortactin axis.
肌营养不良症是一种遗传性肌病，其特征是进行性肌肉无力。最近，已经开发出了几种基因疗法；然而，治疗选择仍然有限。白藜芦醇是 SIRT1 的激活剂，可改善肌营养不良症患者和肌营养不良症缺陷型 mdx 小鼠的肌肉功能，尽管其机制尚未完全阐明。在这里，我们研究了白藜芦醇对膜封闭的影响。我们发现白藜芦醇通过激活 SIRT1 促进 C2C12 细胞的膜修复。为了阐明白藜芦醇促进膜封闭的机制，我们专注于细胞骨架的重组，这发生在膜修复的早期阶段。白藜芦醇处理促进了损伤部位的肌动蛋白积累。我们还研究了 cortactin 在膜封闭中的作用。cortactin 在损伤部位积累，cortactin 敲低抑制了膜封闭和细胞骨架的重组。此外，SIRT1 去乙酰化 cortactin 并促进 cortactin 与 F-actin 的相互作用，从而可能增强 cortactin 在损伤部位的积累。最后，我们使用来自对照和白藜芦醇喂养小鼠的单个纤维肌管进行了膜修复测定，其中白藜芦醇的口服治疗促进了体外的膜修复。这些发现表明，白藜芦醇通过 SIRT1/cortactin 轴促进膜修复。
