Mechanisms of cardiomyopathy in duchenne muscular dystrophy: A study using pluripotent stem cells derived from patients with severe and mild motor impairment

Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder marked by progressive muscle degeneration and early cardiac involvement, with cardiac dysfunction as a major contributor to mortality. However, the molecular mechanisms underlying DMD-associated cardiac dysfunction remain unclear. This study aimed to elucidate these mechanisms and identify gene expression patterns associated with disease progression. Induced pluripotent stem cells (iPSCs) were derived from two patients with DMD exhibiting severe and mild motor impairment and differentiated into cardiomyocytes (iPSC-CMs). The resulting iPSC-CMs expressed myocardial markers, with genetic analysis confirmed dystrophin deficiency in DMD iPSC-CMs. Transcriptomic analysis revealed distinct gene expression profiles, with severe DMD iPSC-CMs exhibiting upregulation of the positive regulation of the transmembrane receptor protein serine/threonine kinase signaling pathway, leading to reduced proliferation, while mild DMD iPSC-CMs showed increased PI3K-Akt signaling and metabolic activity. Severe DMD iPSC-CMs also displayed more pronounced arrhythmicity, with significant correlation between dilated cardiomyopathy signaling changes and heart rate differences. This study establishes an iPSC-CM model for DMD cardiomyopathy, revealing altered gene expression and signaling pathways involved in cardiac dysfunction. Although non-allelic effects and unquantified differentiation efficiency may impact interpretation, these findings highlight key molecular alterations and offer potential therapeutic targets to improve cardiac outcomes in DMD.