Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.
JK, F., P, H., CM, L., A, U., F, K., AJ, K., L, W., L, W., S, H., & MM, D. (2026). Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.. Nature cardiovascular research. https://doi.org/10.1038/s44161-026-00829-z
JK F, P H, CM L, A U, F K, AJ K, et al. Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.. Nature cardiovascular research. 2026; doi: 10.1038/s44161-026-00829-z
JK F, P H, CM L, et al. Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.[J]. Nature cardiovascular research. 2026. DOI: 10.1038/s44161-026-00829-z.
@article{jk2026,
author = {Freundt JK and Hartmann P and Loescher CM and Unger A and Koser F and Klotz AJ and Wildschütz L and Wachsmuth L and Hille S and Door MM},
title = {Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis.},
journal = {Nature cardiovascular research},
year = {2026},
doi = {10.1038/s44161-026-00829-z},
note = {PMID: 42304077},
}
TY - JOUR AU - Freundt JK AU - Hartmann P AU - Loescher CM AU - Unger A AU - Koser F AU - Klotz AJ AU - Wildschütz L AU - Wachsmuth L AU - Hille S AU - Door MM TI - Selective titin cleavage disrupts cardiac mechanical homeostasis to drive heart failure and fibrosis. T2 - Nature cardiovascular research PY - 2026 DO - 10.1038/s44161-026-00829-z AN - PMID:42304077 ER -
Titin, the largest human protein, forms the elastic sarcomeric backbone, providing passive stiffness and length-dependent activation in cardiomyocytes. Whereas titin mutations cause inherited cardiomyopathies, ischemic and chemotherapy-induced injury also provoke proteolytic cleavage of titin's elastic segment. However, the effects of acute titin stiffness loss remain unknown. Here we develop a knock-in mouse enabling in vivo cleavage of cardiac titin springs and use multimodal analysis (cardiac magnetic resonance imaging, echocardiography, microscopy, omics) to show that titin cleavage does not dilate the heart but reduces chamber size and impairs ventricular filling. Mechanical assays of isolated cardiomyocytes reveal diminished restoring forces causing a loss of elastic recoil. In vivo cleavage disrupts junctions, including integrin linkages and connexin 43 gap junctions, widens intermyocyte space without hypertrophy or hyperplasia and drives fibroblast activation, extracellular matrix remodeling and fibrosis. Compensatory mechanisms fail, leading to decompensated heart failure. These findings establish that proteolytic titin cleavage perturbs cardiac mechanical homeostasis, driving disease and matrix stiffening.