Clinical Research Center, National Center for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China; Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing 100875, China.
Department of Biochemistry and Molecular Biology, Beijing Normal University, Gene Engineering Drug and Biotechnology Beijing Key Laboratory, Beijing 100875, China; Beijing Advanced Innovation Center for Genomics (ICG), Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China.
J Proteomics. 2022 Mar 15;254:104477. doi: 10.1016/j.jprot.2021.104477. Epub 2022 Jan 3.
Statin-associated muscle symptoms (SAMS) are the main side effects of statins. Currently, there are no effective biomarkers for accurate clinical diagnosis. Urine is not subject to homeostatic control and therefore accumulates early changes, making it an ideal biomarker source. We therefore examined urine proteome changes associated with SAMS. Here, we established a SAMS rat model by intragastric intubation with simvastatin (80 mg/kg). Biochemical analyses and hematoxylin and eosin staining were used to evaluate the degree of muscle injury. The urine proteome on days 3, 6, 9 and 14 was profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Differential proteins on day 14 of SAMS were mainly associated with glycolysis/gluconeogenesis, pyruvate metabolism, metabolism of reactive oxygen species and apoptosis, which were associated with the pathological mechanism of SAMS. Among the 14 differential proteins on day 3, Fibrinogen gamma chain (FIBG), Osteopontin (OSTP) and C-reactive protein (CRP) were associated with muscle damage, while EH domain-containing protein 1(EHD1), Cubilin (CUBN) and Fibronectin (FINC) were associated with the pathogenic mechanisms of SAMS. Our preliminary results indicated that the urine proteome can reflect early changes in the SAMS rat model, providing the potential for monitoring drug side effects in future clinical research. SIGNIFICANCE: This study demonstrate that the early muscle damage caused by simvastatin can be reflected in urinary proteins. The urine proteome also has the potential to reflect the pharmacology and toxicology of drugs in future clinical research.
他汀类药物相关肌肉症状（SAMS）是他汀类药物的主要副作用。目前，尚无准确临床诊断的有效生物标志物。尿液不受内稳态控制，因此会较早积累变化，使其成为理想的生物标志物来源。因此，我们研究了与 SAMS 相关的尿液蛋白质组变化。在这里，我们通过灌胃给予辛伐他汀（80mg/kg）建立了 SAMS 大鼠模型。生化分析和苏木精-伊红染色用于评估肌肉损伤程度。使用液相色谱-串联质谱（LC-MS/MS）分析第 3、6、9 和 14 天的尿液蛋白质组。SAMS 第 14 天的差异蛋白主要与糖酵解/糖异生、丙酮酸代谢、活性氧代谢和细胞凋亡有关，这些与 SAMS 的病理机制有关。在 SAMS 第 3 天的 14 个差异蛋白中，纤维蛋白原γ链（FIBG）、骨桥蛋白（OSTP）和 C 反应蛋白（CRP）与肌肉损伤有关，而 EH 结构域蛋白 1（EHD1）、穹窿蛋白（CUBN）和纤维连接蛋白（FINC）与 SAMS 的发病机制有关。我们的初步结果表明，尿液蛋白质组可以反映 SAMS 大鼠模型的早期变化，为未来临床研究中监测药物副作用提供了潜力。意义：本研究表明，辛伐他汀引起的早期肌肉损伤可以反映在尿液蛋白中。尿液蛋白质组也有可能在未来的临床研究中反映药物的药理学和毒理学。
