Shen Yuntian, Zhang Qiuyu, Huang Ziwei, Zhu Jianwei, Qiu Jiayi, Ma Wenjing, Yang Xiaoming, Ding Fei, Sun Hualin
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China.
Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, China.
Front Physiol. 2020 Aug 12;11:988. doi: 10.3389/fphys.2020.00988. eCollection 2020.
Although denervated muscle atrophy is common, the underlying molecular mechanism remains unelucidated. We have previously found that oxidative stress and inflammatory response may be early events that trigger denervated muscle atrophy. Isoquercitrin is a biologically active flavonoid with antioxidative and anti-inflammatory properties. The present study investigated the effect of isoquercitrin on denervated soleus muscle atrophy and its possible molecular mechanisms. We found that isoquercitrin was effective in alleviating soleus muscle mass loss following denervation in a dose-dependent manner. Isoquercitrin demonstrated the optimal protective effect at 20 mg/kg/d, which was the dose used in subsequent experiments. To further explore the protective effect of isoquercitrin on denervated soleus muscle atrophy, we analyzed muscle proteolysis the ubiquitin-proteasome pathway, mitophagy, and muscle fiber type conversion. Isoquercitrin significantly inhibited the denervation-induced overexpression of two muscle-specific ubiquitin ligases-muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx), and reduced the degradation of myosin heavy chains (MyHCs) in the target muscle. Following isoquercitrin treatment, mitochondrial vacuolation and autophagy were inhibited, as evidenced by reduced level of autophagy-related proteins (ATG7, BNIP3, LC3B, and PINK1); slow-to-fast fiber type conversion in the target muscle was delayed triggering expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α); and the production of reactive oxygen species (ROS) in the target muscle was reduced, which might be associated with the upregulation of antioxidant factors (SOD1, SOD2, NRF2, NQO1, and HO1) and the downregulation of ROS production-related factors (Nox2, Nox4, and DUOX1). Furthermore, isoquercitrin treatment reduced the levels of inflammatory factors-interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α)-in the target muscle and inactivated the JAK/STAT3 signaling pathway. Overall, isoquercitrin may alleviate soleus muscle atrophy and mitophagy and reverse the slow-to-fast fiber type conversion following denervation inhibition of oxidative stress and inflammatory response. Our study findings enrich the knowledge regarding the molecular regulatory mechanisms of denervated muscle atrophy and provide a scientific basis for isoquercitrin as a protective drug for the prevention and treatment of denervated muscle atrophy.
虽然失神经肌肉萎缩很常见，但其潜在的分子机制仍未阐明。我们之前发现氧化应激和炎症反应可能是触发失神经肌肉萎缩的早期事件。异槲皮苷是一种具有抗氧化和抗炎特性的生物活性黄酮类化合物。本研究调查了异槲皮苷对失神经比目鱼肌萎缩的影响及其可能的分子机制。我们发现异槲皮苷能有效减轻失神经后比目鱼肌的质量损失，且呈剂量依赖性。异槲皮苷在20mg/kg/d时表现出最佳保护作用，后续实验采用该剂量。为进一步探究异槲皮苷对失神经比目鱼肌萎缩的保护作用，我们分析了肌肉蛋白水解、泛素-蛋白酶体途径、线粒体自噬和肌纤维类型转换。异槲皮苷显著抑制失神经诱导的两种肌肉特异性泛素连接酶——肌肉环指蛋白1（MuRF1）和肌肉萎缩F盒蛋白（MAFbx）的过表达，并减少目标肌肉中肌球蛋白重链（MyHCs）的降解。异槲皮苷处理后，线粒体空泡化和自噬受到抑制，这可通过自噬相关蛋白（ATG7、BNIP3、LC3B和PINK1）水平降低得以证明；目标肌肉中慢肌纤维向快肌纤维的类型转换延迟，这触发了过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）的表达；目标肌肉中活性氧（ROS）的产生减少，这可能与抗氧化因子（SOD1、SOD2、NRF2、NQO1和HO1）的上调以及ROS产生相关因子（Nox2、Nox4和DUOX1）的下调有关。此外，异槲皮苷处理降低了目标肌肉中炎症因子白细胞介素（IL）-1β、IL-6和肿瘤坏死因子-α（TNF-α）的水平，并使JAK/STAT3信号通路失活。总体而言，异槲皮苷可能通过抑制氧化应激和炎症反应来减轻比目鱼肌萎缩和线粒体自噬，并逆转失神经后的慢肌纤维向快肌纤维的类型转换。我们的研究结果丰富了关于失神经肌肉萎缩分子调控机制的知识，并为异槲皮苷作为预防和治疗失神经肌肉萎缩的保护药物提供了科学依据。
