BS22 How does filamin C sense mechanical strain?

The Z-disc is a protein rich structure in the cardiac sarcomeres. Its structural role is to tether actin filaments. But equally important, it also plays a crucial role in sensing and responding to mechanical signals. Genetic variants in Z-disc proteins can cause cardiomyopathies. Even though such variants are rare, they help to understand mechano-signalling functions of the Z-disc. Filamin C is an actin crosslinking protein in the Z-disc and postulated to be a mechanosensor in the heart. We have generated two mouse models, one deleting an 80 amino acid module, thought to be part of the mechano-sensing region, and one for a Hypertrophic Cardiomyopathy (HCM) associated variant in this region. Both mouse models were characterised by echocardiography and tissues analysed by qPCR and Western blotting. In line with a late onset phenotype in human patients, the HCM mouse model showed no abnormalities at young age (3 months) in the heterozygous setting. Homozygous mice displayed cardiac dysfunction at 6 months of age when analysed by sensitive strain echocardiography. Mice with the larger deletion showed no overt phenotype at 6 months of age in the heterozygous setting. However, we were not able to generate homozygous mice, suggesting lethality pre- or early postnatally. In both mouse models, markers of the fetal gene programme were upregulated on qPCR. Western blotting identified downregulaton of one specific binding partner in the mice with the larger deletion, while the same protein was normally expressed in the mice with the HCM variant. These mouse models will help to dissect how filamin C contributes to cardiac mechanosignalling and how the process is impaired in cardiomyopathies. Conflict of Interest none