Key result
Cleaving cardiac titin springs impairs ventricular filling and drives fibrosis, leading to decompensated heart failure.
Why the study?
Ischemic and chemotherapy-induced injury provoke proteolytic cleavage of titin's elastic segment, but the effects of acute titin stiffness loss remain unknown.
Does selective in vivo cleavage of cardiac titin springs disrupt cardiac mechanical homeostasis and drive heart failure in a mouse model?
Does selective in vivo cleavage of cardiac titin springs disrupt cardiac mechanical homeostasis and drive heart failure in a mouse model?
Proteolytic cleavage of titin's elastic segment directly impairs cardiomyocyte elastic recoil and ventricular filling, triggering extracellular matrix remodeling and decompensated heart failure.
Titin proteolysis may drive diastolic dysfunction and fibrosis; hypothesis-generating in mice and requires human validation before clinical relevance.
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.
No takes yet. Share an insight, caveat, or question.
Freundt et al. (2026) studied Heart failure and fibrosis. AAV9-mediated TEV expression (in vivo titin cleavage) vs. AAV9-GFP was evaluated on Left ventricular chamber size and ventricular filling. In vivo proteolytic cleavage of cardiac titin springs reduces chamber size, impairs ventricular filling and elastic recoil, and drives fibroblast activation and fibrosis, leading to decompensated heart failure.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: