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

Study investigators encountered a female Becker muscular dystrophy (BMD) carrier with advanced heart failure (HF) and identified a stop-gain variant in procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 ( PLOD3 ) as a potential second-hit variant. Isogenic induced pluripotent stem cells (iPSCs) with dominant expression of WT- DMD , Δ45-48- DMD , or Δ45-48- DMD with corrected PLOD3 variant were established. Microforce testing using 3-dimensional self-organized tissue rings (SOTRs) generated from iPSC-derived cardiomyocytes (iPSC-CMs) demonstrated that correction of the heterozygous PLOD3 variant did not improve the reduced force, but it significantly recovered the reduced stiffness in Δ45-48- DMD SOTRs. Correction of the PLOD3 variant restored collagen synthesis in iPSC-CMs. Our findings revealed the pathogenesis underlying advanced HF in a female BMD carrier.
Competing Interests: This work was supported by JSPS KAKENHI grant numbers 19K08489, 19K12801, 20K21602, 21H02915, and 22K19526, grants-in-aid from the Japanese Ministry of Health, Labor, and Welfare, the Japan agency for medical research and development (21bm0804008h0005, 22bm0804035h0001). This work was also supported by the Cell Science Research Foundation and the Grant for Basic Research of the Japanese Circulation Society (2018), SENSHIN Medical Research Foundation, Daiichi Sankyo, Mitsubishi Tanabe Pharma, and the Center of Medical Innovation and Translational Research and the Center for Medical Research and Education of the Graduate School of Medicine, Osaka University. The Department of Medical Therapeutics for Heart Failure was an endowment department supported by Actelion Pharmaceuticals Japan (2015-2020); the Department of Medical Therapeutics for Heart Failure is currently a Joint Research Department with TOA EIYO Pharmaceutical Company. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(© 2023 The Authors.)