Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients

2020 | journal article; research paper. A publication with affiliation to the University of Göttingen.

Jump to: Cite & Linked | Documents & Media | Details | Version history

Cite this publication

​Troponin destabilization impairs sarcomere-cytoskeleton interactions in iPSC-derived cardiomyocytes from dilated cardiomyopathy patients​
Dai, Y.; Amenov, A.; Ignatyeva, N.; Koschinski, A.; Xu, H.; Soong, P. L.   & Tiburcy, M.  et al.​ (2020) 
Scientific Reports10(1) art. 209​.​ DOI: https://doi.org/10.1038/s41598-019-56597-3 

Documents & Media

s41598-019-56597-3.pdf7.85 MBAdobe PDF41598_2019_56597_MOESM1_ESM.pdf601.29 kBAdobe PDF

License

Published Version

Attribution 4.0 CC BY 4.0

Details

Authors
Dai, Yuanyuan; Amenov, Asset; Ignatyeva, Nadezda; Koschinski, Andreas; Xu, Hang; Soong, Poh Loong ; Tiburcy, Malte ; Linke, Wolfgang A. ; Zaccolo, Manuela; Hasenfuss, Gerd ; Zimmermann, Wolfram-Hubertus ; Ebert, Antje 
Abstract
The sarcomeric troponin-tropomyosin complex is a critical mediator of excitation-contraction coupling, sarcomeric stability and force generation. We previously reported that induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from patients with a dilated cardiomyopathy (DCM) mutation, troponin T (TnT)-R173W, display sarcomere protein misalignment and impaired contractility. Yet it is not known how TnT mutation causes dysfunction of sarcomere microdomains and how these events contribute to misalignment of sarcomeric proteins in presence of DCM TnT-R173W. Using a human iPSC-CM model combined with CRISPR/Cas9-engineered isogenic controls, we uncovered that TnT-R173W destabilizes molecular interactions of troponin with tropomyosin, and limits binding of PKA to local sarcomere microdomains. This attenuates troponin phosphorylation and dysregulates local sarcomeric microdomains in DCM iPSC-CMs. Disrupted microdomain signaling impairs MYH7-mediated, AMPK-dependent sarcomere-cytoskeleton filament interactions and plasma membrane attachment. Small molecule-based activation of AMPK can restore TnT microdomain interactions, and partially recovers sarcomere protein misalignment as well as impaired contractility in DCM TnT-R173W iPSC-CMs. Our findings suggest a novel therapeutic direction targeting sarcomere- cytoskeleton interactions to induce sarcomere re-organization and contractile recovery in DCM.
Issue Date
2020
Journal
Scientific Reports 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | A12: Alternative molekulare Signaltransduktionswege durch Kardiomyopathie-verursachende Troponin-Mutationen 
Working Group
RG Ebert (Cardiovascular Cell Biology and Systems Medicine) 
RG Hasenfuß (Transition zur Herzinsuffizienz) 
RG Linke (Kardiovaskuläre Physiologie) 
RG Tiburcy (Stem Cell Disease Modeling) 
RG Zimmermann (Engineered Human Myocardium) 
ISSN
2045-2322
Language
English

Reference

Citations


Social Media