Beyond the sarcomere: the role of biomechanical stress signalling in cardiomyopathies

Speaker: Dr Katja Gehmlich, Division of Cardiovascular Medicine, University of Oxford

Host:  Elisabeth Ehler

Abstract: Cardiomyocytes sense and respond to biomechanical stress through complex signalling cascades. Genetic mutations in proteins involved in these biomechanical stress signalling pathways can cause perturbations in cardiac function, leading to cardiomyopathies. With the help of mouse models and cellular experiments, my group explores the consequences of such mutations. As examples, a missense mutation in Muscle LIM Protein and a missense mutation in the giant protein titin and their consequences on cardiomyocytes will be discussed. The C58G missense mutation in Muscle LIM Protein causes Hypertrophic Cardiomyopathy and functional work has revealed that protein destabilisation and a proteotoxic response contribute to the phenotype. The A178D missense mutation in titin was identified in a family characterised by Left Ventricular Non-Compaction and Dilated Cardiomyopathy. As identified in a mouse model, the disturbed interaction with the ligand telethonin at the Z-disk appears to be the driver of disease in this case.