Titin-truncating variants in hiPSC cardiomyocytes induce pathogenic proteinopathy and sarcomere defects with preserved core contractile machinery
Guanyi Huang, Anjali Bisaria, Devin L. Wakefield, Tracy Yamawaki, Xin Luo, Jingli A. Zhang, Patrick Vigneault, Jinghong Wang, Jeffrey D. Reagan, Oliver Oliverio, Hong Zhou, Chi-Ming Li, Olaia F. Vila, Songli Wang, Fady I. Malik, James J. Hartman, Christopher M. Hale
Abstract
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.
Topics & Concepts
SarcomereTitinInduced pluripotent stem cellBiologyCell biologyTranscriptomeContractilityMyocytePhenotypeMyosinActinActininGeneticsGeneEmbryonic stem cellCellCytoskeletonGene expressionEndocrinologyCardiomyopathy and Myosin StudiesAdvanced biosensing and bioanalysis techniquesRNA and protein synthesis mechanisms