Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function
Copyright policy )Deleting titin’s I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function
Significance Mutations in titin are a major cause of heart failure, yet the functions of large parts of titin are not understood. Here we studied titin’s I-band/A-band junction that has been proposed to be crucial for thick filament length control. We made a mouse in which titin’s IA junction was deleted. Super-resolution microscopy (structured illumination microscopy) revealed that deleting the IA junction increases the strain on titin’s molecular spring elements without altering thick filament length. Single cell biomechanical measurements showed that this increases passive stiffness while functional studies at the whole animal level revealed diastolic dysfunction, exercise intolerance, and modest concentric cardiac hypertrophy—signature features of heart failure with preserved ejection fraction. Our studies support that titin is a promising therapeutic target for treating heart failure.
- University of Arizona United States
Mice, Knockout, Gene Expression Profiling, Myocardium, Blotting, Western, Molecular Sequence Data, Blood Pressure, Heart, Mechanotransduction, Cellular, Biomechanical Phenomena, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Echocardiography, Linear Models, Animals, Connectin, Myocytes, Cardiac, Amino Acid Sequence, Microscopy, Immunoelectron, Muscle, Skeletal, Cells, Cultured
Mice, Knockout, Gene Expression Profiling, Myocardium, Blotting, Western, Molecular Sequence Data, Blood Pressure, Heart, Mechanotransduction, Cellular, Biomechanical Phenomena, Mice, Inbred C57BL, Microscopy, Electron, Transmission, Echocardiography, Linear Models, Animals, Connectin, Myocytes, Cardiac, Amino Acid Sequence, Microscopy, Immunoelectron, Muscle, Skeletal, Cells, Cultured
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