Abstract：
Skeletal muscle atrophy is a common complication of chronic kidney disease (CKD) that affects the quality of life and prognosis of patients. We aimed to investigate the effects and mechanisms of caffeic acid (CA), a natural phenolic compound, on skeletal muscle atrophy in CKD rats. Male Sprague-Dawley rats underwent 5/6 nephrectomy (NPM) and were treated with CA (20, 40, or 80 mg/kg/day) for 10 weeks. The body and muscle weights, renal function, hemoglobin, and albumin were measured. The histological, molecular, and biochemical changes in skeletal muscles were evaluated using hematoxylin-eosin staining, quantitative real-time PCR, malondialdehyde/catalase/superoxide dismutase/glutathione level detection, and enzyme-linked immunosorbent assay. Western blotting and network pharmacology were applied to identify the potential targets and pathways of CA, CKD, and muscle atrophy. The results showed that CA significantly improved NPM-induced muscle-catabolic effects, reduced the expression of muscle atrophy-related proteins (muscle atrophy F-box and muscle RING finger 1) and proinflammatory cytokines (interleukin [IL]-6, tumor necrosis factor-alpha, and IL-1β), and attenuated muscle oxidative stress. Network pharmacology revealed that CA modulated the response to oxidative stress and nuclear factor kappa B (NF-κB) signaling pathway and that Toll-like receptor 4 (TLR4) was a key target. In vivo experiment confirmed that CA inhibited the TLR4/myeloid differentiation primary response 88 (MYD88)/NF-kB signaling pathway, reduced muscle iron levels, and restored glutathione peroxidase 4 activity, thereby alleviating ferroptosis and inflammation in skeletal muscles. Thus, CA might be a promising therapeutic agent for preventing and treating skeletal muscle atrophy in CKD by modulating the TLR4/MYD88/NF-κB pathway and ferroptosis.
摘要：
骨骼肌萎缩是慢性肾脏病（CKD）的常见并发症，影响患者的生活质量和预后。我们旨在研究咖啡酸（CA）的作用和机制，一种天然酚类化合物,CKD大鼠骨骼肌萎缩的研究.雄性Sprague-Dawley大鼠接受5/6肾切除术（NPM），并用CA（20、40或80mg/kg/天）治疗10周。身体和肌肉的重量，肾功能,血红蛋白,和白蛋白进行测量。组织学，分子，使用苏木精-伊红染色评估骨骼肌的生化变化，实时定量PCR,丙二醛/过氧化氢酶/超氧化物歧化酶/谷胱甘肽水平检测,和酶联免疫吸附测定。应用Westernblotting和网络药理学来确定CA的潜在靶标和途径。CKD,肌肉萎缩.结果表明，CA显著改善了NPM诱导的肌肉分解代谢效应，减少肌肉萎缩相关蛋白（肌肉萎缩F-box和肌肉RING指1）和促炎细胞因子（白细胞介素[IL]-6，肿瘤坏死因子-α，和IL-1β），和减轻肌肉氧化应激。网络药理学显示，CA调节氧化应激和核因子κB（NF-κB）信号通路的反应，Toll样受体4（TLR4）是关键靶标。体内实验证实CA抑制TLR4/髓样分化初发反应88(MYD88)/NF-kB信号通路,降低肌肉铁水平，并恢复了谷胱甘肽过氧化物酶4的活性，从而减轻骨骼肌的铁性凋亡和炎症。因此，CA可能是通过调节TLR4/MYD88/NF-κB通路和铁凋亡来预防和治疗CKD骨骼肌萎缩的有希望的治疗剂。
