Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation

Petr G. Vikhorev, Natalia N. Vikhoreva, Wai Chun Yeung, Amy Li, Sean Lal, Cristobal G. Dos Remedios, Cheavar A. Blair, Maya Guglin, Kenneth S. Campbell, Magdi H. Yacoub, Pieter De Tombe, Steven B. Marston

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Aims: Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants. Methods and results: We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants. Conclusion: Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.

Original languageEnglish
Pages (from-to)241-253
Number of pages13
JournalCardiovascular Research
Issue number1
StatePublished - Jan 1 2022

Bibliographical note

Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.


  • Cardiac contractility and energetics
  • Dilated cardiomyopathy
  • Length-dependent activation
  • Super- relaxed state of myosin
  • Titin

ASJC Scopus subject areas

  • Medicine (all)


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