Multiomics Analyses of Steroid Drug Efficacy in Duchenne Muscular Dystrophy Cardiomyocytes

Duchenne muscular dystrophy (DMD) is an X-linked degenerative disorder that causes progressive damage to skeletal and cardiac muscles, ultimately leading to premature mortality. The recently approved drug vamorolone (Agamree) demonstrates comparable efficacy in motor function improvement to conventional glucocorticoids, such as prednisolone, but with markedly reduced side effects. Unlike many corticosteroids that increase blood volume and pressure, vamorolone exhibits cardioprotective properties. However, molecular characterization of these effects has been challenging because traditional DMD models, including the mdx mouse, fail to manifest the cardiac disease phenotypes observed in patients. Here, we established a representative dystrophic cardiomyopathy model by differentiating DMD patient-derived induced pluripotent stem cells into cardiomyocytes (DMD-CMs). Compared with healthy control CMs, DMD-CMs exhibited downregulated transcriptional signatures resulting in extracellular matrix stability, cardiac action potential regulation and cytoskeletal integrity. Using this disease model, we further assessed vamorolone treatment compared to other corticosteroids (prednisone, eplerenone, and aldosterone) using RNA-sequencing and high-resolution mass spectrometry-based metabolomics. All drug treatments altered the abundance of metabolites in the methionine cycle and downstream pathways in DMD-CMs. Vamorolone reprogrammed the transcriptional profiles associated with mitochondrial function, redox homeostasis, ER stress response, and actin binding when compared to prednisolone-treated DMD-CMs. Our gene-metabolite network analyses reveal that prednisolone significantly enhanced inflammatory processes and metabolically rewired the TCA flux shifting toward anaerobic glycolysis. Taken together, this represents the first integrated transcriptomic and metabolic analysis delineating the DMD cardiac