Modeling Reduced Contractility and Stiffness Using iPSC-Derived Cardiomyocytes Generated From Female Becker Muscular Dystrophy Carrier

This study investigated the biomechanical basis of advanced heart failure in a rare female Becker muscular dystrophy (BMD) carrier using isogenic induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Three-dimensional self-organized tissue rings (SOTRs) were generated from cardiomyocytes expressing wild-type dystrophin, truncated dystrophin (D45–48), or corrected PLOD3 variants. Microforce testing revealed significantly reduced contractile force and passive stiffness in D45–48 dystrophin tissues, with stiffness partially restored following correction of the PLOD3 variant. The findings demonstrate that combined defects in dystrophin structure and collagen synthesis contribute to impaired cardiac mechanics and provide a mechanistic model of cardiomyopathy progression in female BMD carriers.