Deciphering the mechano-genomic pathway of striated muscle

The linker of the nucleoskeleton and cytoskeleton (LINC) complex transmits mechanical signals from the cytoplasm into the nucleus, enabling transcriptional responsivity to changing mechanical environments. Human mutations in various LINC components are associated with diseases of mechanically active tissues including the heart, and disrupting the LINC complex may be cardioprotective in myopathies driven by nuclear fragility. Despite this growing translational relevance, the nuclear mechanotransduction pathway in the mature muscle is not well established. Live, in-vivo imaging of Drosophila larva myonuclei demonstrates that proper 3D chromatin organization depends on a functional LINC complex and the composition of the nuclear lamina, and reveals enlarged hubs of epigenetically repressed chromatin upon LINC complex mutation. Biophysical analysis and super-resolution imaging in isolated adult murine cardiomyocytes reveals reduced nuclear strain transfer in beating cardiomyocytes when the LINC complex is perturbed, accompanied by downstream effects on nuclear mRNA export, nuclear morphology, and chromatin reorganization with increased repression and chromatin translocation from the lamina to nucleoli associated domains. Current work is focused on in-vivo perturbations of the LINC complex in the mature heart and on identifying the precise molecular interactions between cytoskeletal and nucleoskeletal proteins. Together, these studies identify a novel role of the LINC complex in regulation of genome organization and repression in striated muscle and help to dissect specific pathways of mechanical signal transmission into the nucleus which are required to advance the treatment of laminopathies.