Regulation of titin-based cardiac stiffness by unfolded domain oxidation (UnDOx)
| Autor: | Martina Krüger, Sebastian Kötter, Alexander Dietl, Andreas Unger, Alexander Nickel, Belal A. Mohamed, Lars I. Leichert, Christoph Maack, Christine M Loescher, Martin Breitkreuz, Andreas J. Schmidt, Yong Li, Karl Toischer, Nazha Hamdani, Wolfgang A. Linke, Joachim P. Schmitt, Marcus Krüger |
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| Rok vydání: | 2020 |
| Předmět: |
Male
animal structures Physiology single-molecule measurements macromolecular substances Immunoglobulin domain Turn (biochemistry) proteomics medicine Disulfide bonding Animals Myocytes Cardiac Phosphorylation Passive stiffness Multidisciplinary biology Chemistry Myocardium Stiffness Biological Sciences musculoskeletal system Elasticity myocardial stiffness Mice Inbred C57BL Folding (chemistry) Oxidative Stress embryonic structures cardiovascular system biology.protein Biophysics Titin medicine.symptom Oxidation-Reduction Protein Kinases tissues mechanics |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.2004900117 |
| Popis: | Significance Titin oxidation alters titin stiffness, which greatly contributes to overall myocardial stiffness. This stiffness is frequently increased in heart disease, such as diastolic heart failure. We have quantified the degree of oxidative titin changes in several murine heart and skeletal muscle models exposed to oxidant stress and mechanical load. Importantly, strain enhances in vivo oxidation of titin in the elastic region, but not the inextensible segment. The functional consequences include oxidation type-dependent effects on cardiomyocyte stiffness, titin-domain folding, phosphorylation, and inter-titin interactions. Thus, oxidative modifications stabilize the titin spring in a dynamic and reversible manner and help propagate changes in titin-based myocardial stiffness. Our findings pave the way for interventions that target the pathological stiffness of titin in disease. 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. |
| Databáze: | OpenAIRE |
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