Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery


Titin-truncating variants (TTNtv) are the single largest genetic cause of dilated cardiomyopathy (DCM). In this study we modeled disease phenotypes of A-band TTNtv-induced DCM in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) using genome editing and tissue engineering technologies. Transcriptomic, cellular, and micro-tissue studies revealed that A-band TTNtv hiPSC-CMs exhibit pathogenic proteinopathy, sarcomere defects, aberrant Na+ channel activities, and contractile dysfunction. These phenotypes establish a dual mechanism of poison peptide effect and haploinsufficiency that collectively contribute to DCM pathogenesis. However, TTNtv cellular defects did not interfere with the function of the core contractile machinery, the actin-myosin-troponin-Ca2+ complex, and preserved the therapeutic mechanism of sarcomere modulators. Treatment of TTNtv cardiac micro-tissues with investigational sarcomere modulators augmented contractility and resulted in sustained transcriptomic changes that promote reversal of DCM disease signatures. Together, our findings elucidate the underlying pathogenic mechanisms of A-band TTNtv-induced DCM and demonstrate the validity of sarcomere modulators as potential therapeutics. Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Authors Huang G, Bisaria A, Wakefield DL, Yamawaki TM, Luo X, Zhang JA, Vigneault P, Wang J, Reagan JD, Oliverio O, Zhou H, Li CM, Vila OF, Wang S, Malik FI, Hartman JJ, Hale CM
Journal Stem cell reports
Publication Date 2023 Jan 10;18(1):220-236
PubMed 36525964
PubMed Central PMC9860080
DOI 10.1016/j.stemcr.2022.11.008

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