Dynamic urine proteome changes in a rat model of simvastatin-induced skeletal muscle injury

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.