Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Monday Speaker Abstracts

MICROTUBULES ARE VISCOUS REGULATORS OF MYOCARDIAL MOTION Matthew A. Caporizzo 1 ; 1 The University of Vermont, Molecular Physiology and Biophysics, Burlington, VT, USA Diastolic dysfunction is a common and untreatable feature of heart failure that arises from increased ventricular stiffness and impaired relaxation. Recent evidence has emerged that the cardiac microtubule network densifies in end-stage heart failure reducing the shortening and relaxation velocities of failing cardiomyocytes. As microtubules are known regulators of cellular mechanotransduction, we hypothesized that microtubule stabilization occurs during the progression of diastolic heart disease (DHD). To determine if microtubule stabilization is involved in the progression of diastolic heart disease, we quantified microtubule network remodeling and its contribution to myocyte active and passive mechanics in rat models of hypertension and diastolic heart failure. Our results indicate that both hypertensive and DHD rats exhibit proportional increases in microtubule network density and detyrosination. Cardiomyocyte size and viscoelastic stiffness was increased in both hypertensive and DHD myocytes while reduced relaxation velocity was only observed in DHD myocytes. Intervention to reduce microtubule detyrosination was sufficient to partially restore myocyte viscoelasticity and contractile velocity. Together these changes indicate that microtubule stabilization occurs in both HTN and DHD and intervention targeting stable microtubules is sufficient to partially reverse myocyte stiffening and impaired relaxation.

REGULATING TITIN BASED STIFFNESS IN HEALTH AND DISEASE Michael Gotthardt ; 1 Max Delbrück Center for Molecular Medicine, Translational Cardiology and Functional Genomics, Berlin, Germany 2 Charité Universitätsmedizin Berlin, Department of Cardiology, Angiology and Intensive Care Medicine, Berlin, Germany The giant Titin protein plays a crucial role in maintaining the passive stiffness of the muscle and the response to mechanical load. Titin based stiffness is tightly regulated by various factors such as post-translational modifications, alternative splicing, and proteolysis. In healthy individuals, this regulation is essential for the normal functioning of the heart and skeletal muscle. However, alterations in titin-based stiffness have been associated with various pathological conditions such as cardiomyopathy, muscular dystrophy, and heart failure. We have used a series of animal models eliminating select spring regions to dissect trophic from mechanosignaling and developed a splice therapeutic approach to reduce titin based stiffness in cardiac disease.

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