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

Kameda S, Higo S, et al.

JACC: Basic to Translational Science

Osaka University Graduate School of Medicine, Osaka Police Hospital, National Cerebral and Cardiovascular Center

RESEARCH SUMMARY

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.

Microforce mechanical testing was performed using a CellScale MicroTester G2 to quantify both active contractile force and passive stiffness of three-dimensional self-organized tissue rings formed from iPSC-derived cardiomyocytes. Tissue rings were mounted on cantilever hooks and subjected to controlled stepwise tensile stretching, enabling measurement of twitch force generation and length-dependent passive stiffness. This ultra-low-force testing approach allowed precise characterization of cardiomyocyte tissue mechanics relevant to physiological cardiac loading and mechanotransduction.

AUTHORS

Satoshi Kameda; Shuichiro Higo; Mikio Shiba; Takumi Kondo; Junjun Li; Li Liu; Tomoka Tabata; Hiroyuki Inoue; Shota Okuno; Shou Ogawa; Yuki Kuramoto; Hideki Yasutake; Jong-Kook Lee; Seiji Takashima; Yoshihiko Ikeda; Shungo Hikoso; Shigeru Miyagawa; Yasushi Sakata.

PUBLICATION DETAILS

JOURNAL

JACC: Basic to Translational Science

YEAR

2023

INSTITUTIONS

Osaka University Graduate School of Medicine, Osaka Police Hospital, National Cerebral and Cardiovascular Center

COUNTRIES

Japan

INSTRUMENT USED

MicroTester

TESTING METHODS

Micro-Mechanical TestingTensile TestingUltra Low Force TestingViscoelastic & Time-Dependent Testing

RESEARCH APPLICATIONS

Cardiac Tissue Engineering & MechanicsFibrosis & Tissue RemodelingMechanotransductionOrganoid and Tissue Mimetic SystemsStem Cell Mechanobiology

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