Biomechanical Isolation is Required for Maintenance of the Cardiac Pacemaker Cell Fate

Electrical impulses initiated within the sinoatrial node (SAN) drive rhythmic beating of the heart. These electrical impulses are generated by specialized cardiomyocytes termed cardiac pacemaker cells (CPCs). While the ionic mechanisms that control CPC function have long been studied, the upstream cellular events that pattern and maintain the unique electrophysiological properties of the SAN remain poorly understood. Using quantitative proteomic approaches, we have identified that developing CPCs lack fundamental components of the molecular machinery necessary to sense and respond to mechanical signaling cues. Furthermore, we have identified that ectopic activation of the core mechanotransduction pathways within CPCs induces severe SAN electrical dysfunction. Mechanistically, we demonstrate that entire systems of ion channels required for electrical oscillation and the major transcription factor networks associated with CPC cell lineage commitment are rapidly downregulated in response to cellular strain. These data reveal that the mechanical uncoupling and/or suppression of mechano-transductive signaling pathways represent a previously unrecognized critical regulatory mechanism required to support cardiac pacemaking.