A Performance Evaluation of Liver and Skeletal Muscle-Specific miRNAs in Rat Plasma to Detect Drug-Induced Injury

Abstract

Liver and skeletal muscle-specific microRNAs (miRNAs) are currently being evaluated as novel plasma biomarkers that may out-perform or add value to the conventional liver injury biomarkers alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and to the skeletal muscle injury biomarkers AST and creatine kinase (CK). A comprehensive evaluation was conducted to assess the relative performance of these miRNAs to detect and distinguish liver from muscle tissue injury. The performance of miR-122 and miR-192 for liver and miR-1, miR-133a, miR-133b, and miR-206 for skeletal muscle was compared with 10 enzymatic or protein biomarkers across 27 compounds causing specific types of tissue injury in rat. Receiver operator characteristic analyses were performed comparing the relative sensitivity and specificity of each of the biomarkers in individual animals with histopathology observations of necrosis and/or degeneration in various organs. All of the miRNAs outperformed ALT, AST, and/or CK in studies with either liver or skeletal muscle injury and demonstrated superior specificity in organs without type-specific injury (eg, liver biomarkers assessed with compounds that cause skeletal muscle injury). When additional protein biomarkers were included, glutamate dehydrogenase, arginase I, alpha-glutathione S-transferase for liver and skeletal troponin I, myosin light chain 3, fatty acid-binding protein 3, and creatine kinase M isoform for skeletal muscle, the miRNAs demonstrated equal or superior performance to the extended panel. Taken together, this comprehensive evaluation demonstrates that these novel miRNA toxicity biomarkers outperform and add value with respect to sensitivity and specificity over ALT, AST in monitoring the liver and over CK for monitoring skeletal muscle drug-induced injury.

Keywords: DILI; biomarker; liver; miR-1; miR-122; miR-133; miR-192; miR-206; skeletal muscle.