Skeletal Muscle Injury Biomarkers: Assay Qualification Efforts and Translation to the Clinic.

Skeletal muscle (SKM) injury or myopathy results in structural or functional defects in SKMs that can be caused by variety of factors such as (1) genetic, (2) drug-induced, (3) disease progression (cachexia), or (4) aging (sarcopenia). Creatine kinase (CK) and aspartate transaminase (AST) activity assays have been routinely used as SKM injury biomarkers, but they lack sensitivity and tissue specificity. In collaboration with the Predictive Safety Testing Consortium, we evaluated the diagnostic performance of a muscle injury biomarker panel (MIP) compared to CK and AST and their correlation with the histology scores across 34 different rat studies. The MIP panel included the analytes skeletal troponin I, myosin light chain 3, fatty acid binding protein 3, and a CK mass (versus activity) assay. The area under the receiver operator characteristic curve for MIP panel ranged from 0.82 to 0.91 as compared to 0.71 and 0.82 for CK and AST activity assays, respectively. Because the MIP biomarkers outperformed the routine biomarkers, the European Medicines Agency and U.S. Food and Drug Administration posted Letters of Support encouraging further study of these analytes and acknowledged the utility of the MIP panel. Ongoing efforts are directed toward the application of the MIP panel biomarkers in clinical studies and regulatory qualification.