Longitudinal Assessment of Creatine Kinase, Creatine/Creatinineratio, and Myostatin as Monitoring Biomarkers in Becker Muscular Dystrophy

Background and Objectives: The slow and variable disease progression of Becker muscular dystrophy (BMD) urges the development of biomarkers to facilitate clinical trials. We explored changes in three muscle-enriched biomarkers in serum of BMD patients over 4 years-time and studied associations with disease severity, disease progression and dystrophin levels in BMD. Methods: We quantitatively measured creatine kinase (CK) using the IFCC reference method, creatine/creatinineratio (Cr/Crn) using liquid chromatography – tandem mass spectrometry (LC-MS/MS) and myostatin with ELISA in serum, and assessed functional performance using North Star Ambulatory Assessment (NSAA), ten-meter run velocity (TMRv), six-minute walking test (6MWT), and Forced Vital Capacity (FVC) in a 4-year prospective natural history study. Dystrophin levels were quantified in the tibialis anterior muscle using capillary Western immunoassay. The correlation between biomarkers, age, functional performance, mean annual change, and prediction of concurrent functional performance were analyzed using linear mixed models. Results: Thirty-four patients with 106 visits were included. Eight patients were non-ambulant at baseline. Cr/Crn and myostatin were highly patient-specific (intraclass correlation coefficient for both=0.960). Cr/Crn was strongly negatively correlated, while myostatin was strongly positively correlated with NSAA, TMRv and 6MWT (Cr/Crn rho=-0.869 to -0.801 and myostatin rho=0.792 to 0.842, all p<0.001). CK showed a negative association with age (p=0.0002) but was not associated with patients’ performance. Cr/Crn and myostatin correlated moderately with average annual change of 6MWT (rho=-0.532 and 0.555, p=0.02). Dystrophin levels did not correlate with the selected biomarkers nor with performance. Cr/Crn, myostatin and age could explain up to 75% of the variance of concurrent functional performance of the NSAA, TMRv and 6MWT. Discussion: Both Cr/Crn and myostatin could potentially serve as monitoring biomarkers in BMD as higher Cr/Crn and lower myostatin were associated with lower motor performance and predictive of concurrent functional performance when combined with age. Future studies are needed to more precisely determine the context of use of these biomarkers.