Exploring the role of Z-disk structure and signalling for striated muscle integrity with the help of genome-edited mouse models of cardiomyopathy

The Z-disk is not only a crucial structural part of the sarcomere, but also thought to be a signalling hub for sensing and responding to biomechanical stress. This is highlighted by the fact that mutations in Z-disk proteins can cause inherited heart or skeletal muscle disease, however the underlying signalling pathways are poorly understood.

We have identified missense mutations in Z-disk proteins causing cardiomyopathies. In vivo animal models carrying these mutations will be generated and cardiac phenotyping be performed. Additionally the models will be challenged by e.g. chronic stimulation of adrenergic pathways or through aortic constriction. Ex vivo studies on the hearts from these models will be used to gain insight into disturbance of Z-disk structure and signalling functions. In addition to hypothesis-driven experiments, RNAseq and mass spectrometry approaches will generate novel hypotheses how disturbed Z-disk signalling results in cardiac disease. Newly identified pathways will also be explored in skeletal muscle should the animals display a skeletal muscle phenotype.