Cardiomyocyte mechanical memory is regulated through the talin interactome and DLC1 dependent regulation of RhoA

Abstract

Mechanical properties are cues for many biological processes in health or disease. Likewise, in the heart it is becoming clearer that mechanical signals are critically involved in the disease progression. Cardiomyocytes sense the mechanical properties of their environment at costameres through integrins and associated proteins, including the mechanosensitive protein talin as an integral component. Our previous work indicated different modes of talin tension, depending on the extracellular matrix stiffness. Here, we wanted to study how this leads to downstream mechanotransduction changes, further influencing the cardiomyocyte phenotype. Combining immunoprecipitations and Fluorescence Recovery after Photobleaching (FRAP) experiments, we identify that the talin interacting proteins DLC1, RIAM and paxillin each preferentially bind to talin at specific extracellular matrix stiffness and this interaction is preserved even in absence of tension. This demonstrates a mechanical memory, which we confirm further in vivo in mouse hearts. The mechanical memory is regulated through adhesion related kinase pathways. Optogenetic experiments using the LOVTRAP systems confirm direct competition between the individual proteins, which again is altered through phosphorylation. DLC1 regulates RhoA activity in a stiffness dependent way and both loss and overexpression of DLC1 results in myofibrillar disarray. Together the study demonstrates a mechanism of imprinting mechanical information into the talin-interactome to finetune RhoA activity, with impacts on cardiac health and disease.

The structure of an Amyloid Precursor Protein/talin complex indicates a mechanical basis of Alzheimer's Disease.

“…In this theory, these switch patterns represent a binary code the cell uses to spatially organise the enzymatic processes in the synapse to coordinate synaptic activity (Ball et al, 2024;Barnett and Goult, 2022). Currently, the role of talin in synaptic regulation and memory is not well studied, however, the role of talin in mechanical memory in other systems has been demonstrated experimentally (Dahal et al, 2022;Marhuenda et al, 2023).…”