Becker Muscular Dystrophy (BMD) is caused by in-frame mutations in the DMD gene, leading to the production of internally truncated but partially functional dystrophin. Although cardiac involvement is a major contributor to disease burden in BMD, the cellular mechanisms driving cardiomyopathy remain incompletely understood. While emerging evidence suggests that iron imbalance may contribute to oxidative stress and mitochondrial dysfunction in muscular dystrophies, its role in BMD-associated cardiomyopathy has not been defined. Building on our previous findings of dysregulated iron homeostasis in dystrophin-deficient cardiomyocytes from Duchenne muscular dystrophy (DMD), we investigated whether similar alterations are present in BMD using patient-specific and genome-corrected hiPSC-CM models. HiPSC lines derived from two BMD patients and their CRISPR/Cas9-corrected isogenic controls displayed normal karyotype, pluripotency, and efficient differentiation into cardiomyocytes (hiPSC-CMs). BMD hiPSC-CMs showed elevated ROS levels and decreased cytoplasmic and mitochondrial labile iron pools, accompanied by reduced expression of mitoNEET (CISD1), a regulator of mitochondrial iron handling. We also detected changes in the expression of genes involved in iron storage (FTH1), uptake (TFRC), and export (SLC40A1), suggesting a dysregulation of iron trafficking. Importantly, correction of DMD mutation by CRISPR/Cas9 gene editing reversed the effects observed in BMD cardiomyocytes. These results extend our previous observations in DMD to BMD cardiomyocytes and suggest that full-length dystrophin is essential for maintaining cardiac iron homeostasis.
Keywords: BMD; CISD1; cardiomyopathy; hiPSC; hiPSC-CM; iron overload; mitoNEET.