基于肌蛋白降解和再生平衡探讨芪参颗粒防治慢性心力衰竭合并骨骼肌萎缩的机制研究

Chronic heart failure combined with skeletal muscle wasting directly affects the prognosis of heart failure. Ang II promotes the degradation of muscle protein, inhibits muscle regeneration and causes skeletal muscle wasting. Our previous works suggest that Qishen Granule could prevent heart failure by reducing Ang II, alleviating inflammatory response and promoting AT2R expression. We put forward the scientific hypothesis: Qishen Granule could inhibit skeletal muscle wasting by reducing Ang II and inflammatory factors release, up-regulating the PI3K/Akt signaling pathway and decreasing muscle wasting-related protein expression. Meanwhile, Qishen Granule could promote skeletal muscle regeneration by increasing AT2R expression of muscle satellite cells and down-regulating MEK/ERK1/2 signaling pathway, maintaining muscle volume balance. The rat model of chronic heart failure combined with skeletal muscle wasting and primary muscle satellite cells culture will be used in this project. Histologic and molecular biological methods will be in involved to detect heart function, muscle strength and structure, muscle wasting related proteins, Ang II and its receptors, inflammatory factors, muscle satellite cells proliferation and differentiation, and the signaling pathways. All of these will elucidate the mechanism of Qishen Granule in preventing and treating chronic heart failure combined with skeletal muscle wasting by inhibiting muscle protein degradation and promoting muscle regeneration. This study provides a scientific basis for traditional Chinese medicine in preventing and treating chronic heart failure combined with skeletal muscle wasting, and also offers new ideas and methods for clinical treatment.

慢性心力衰竭合并骨骼肌萎缩直接影响心衰的预后。AngⅡ促进肌蛋白降解，抑制肌再生，导致骨骼肌萎缩。前期工作提示，芪参颗粒能降低AngⅡ，减轻炎性反应，促进AT2R表达而防治心力衰竭。提出科学假说：芪参颗粒通过减少AngⅡ和炎症因子释放，上调PI3K/Akt信号通路，降低萎缩相关蛋白的表达，抑制骨骼肌萎缩；同时增加肌卫星细胞上AT2R表达，下调MEK/ERK1/2信号通路，促进骨骼肌再生，进而维持肌肉容量的平衡。本项目采用大鼠慢性心力衰竭合并骨骼肌萎缩模型和肌卫星细胞原代培养，采用病理、分生等方法，检测心脏功能、骨骼肌力量和结构、萎缩相关蛋白表达、AngⅡ及其受体、炎性因子、肌卫星细胞增殖和分化及相关信号通路，以阐明芪参颗粒通过抑制肌蛋白降解，促进肌再生，防治慢性心力衰竭合并骨骼肌萎缩的作用机制。本研究为中医药防治慢性心力衰竭合并骨骼肌萎缩提供了科学依据，也为临床治疗提供新思路和新方法。

慢性心力衰竭（CHF）是多种心血管疾病发生发展的最终阶段。运动耐量的降低是CHF患者最常见的症状之一，表现为活动后出现疲劳乏力和呼吸困难等，而这一系列症状的出现不仅是患者心脏射血分数降低的原因,还与患者的骨骼肌萎缩密切相关。骨骼肌萎缩不仅导致CHF患者日常生活受到限制，还显著增加其死亡率，严重影响着患者的病情进展和预后。因此，在心衰的治疗上既要改善心功能，又要防治骨骼肌萎缩。本项目通过建立心衰合并骨骼肌萎缩动物模型和L6细胞萎缩模型，从体内和体外两方面研究芪参颗粒对心衰合并骨骼肌萎缩的防治效果和作用机制。主要结果如下：动物实验表明芪参颗粒能减少AngⅡ和炎症因子的生成，降低肌萎缩相关蛋白FOXO1、Atrogin-1和MuRF-1的表达，抑制骨骼肌蛋白的降解；同时，芪参颗粒能升高AT2R的表达，进而增加MyoD和MyoG的表达，促进肌卫星细胞分化，改善骨骼肌的修复和再生。细胞实验提示芪参颗粒不仅能上调PI3K/Akt信号通路抑制骨骼肌蛋白的降解，还能下调MEK/ERK信号通路促进肌再生。该项目为临床防治心衰合并骨骼肌萎缩及其药物开发提供了思路与方法。