Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx)

Christine M. Loescher, Martin Breitkreuz, Yong Li, Alexander Nickel, Andreas Unger, Alexander Dietl, Andreas Schmidt, Belal A. Mohamed, Sebastian Kötter, Joachim P. Schmitt, Marcus Krüger, Martina Krüger, Karl Toischer, Christoph Maack, Lars I. Leichert, Nazha Hamdani, Wolfgang A. Linke

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

The relationship between oxidative stress and cardiac stiffness is thought to involve modifications to the giant muscle protein titin, which in turn can determine the progression of heart disease. In vitro studies have shown that S-glutathionylation and disulfide bonding of titin fragments could alter the elastic properties of titin; however, whether and where titin becomes oxidized in vivo is less certain. Here we demonstrate, using multiple models of oxidative stress in conjunction with mechanical loading, that immunoglobulin domains preferentially from the distal titin spring region become oxidized in vivo through the mechanism of unfolded domain oxidation (UnDOx). Via oxidation type-specific modification of titin, UnDOx modulates human cardiomyocyte passive force bidirectionally. UnDOx also enhances titin phosphorylation and, importantly, promotes nonconstitutive folding and aggregation of unfolded domains. We propose a mechanism whereby UnDOx enables the controlled homotypic interactions within the distal titin spring to stabilize this segment and regulate myocardial passive stiffness.

Original languageEnglish
Pages (from-to)24545-24556
Number of pages12
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number39
DOIs
StatePublished - 29 Sep 2020
Externally publishedYes

Keywords

  • Mechanics
  • Myocardial stiffness
  • Oxidative stress
  • Proteomics
  • Single-molecule measurements

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