Jason W. Rocks

Mechanical signaling coordinates the embryonic heartbeat

Significance There is a mounting body of evidence that physical forces induce biochemical changes. Here, we suggest that the early embryonic heart provides a striking illustration of the importance of mechanics in living matter. Whereas adult hearts use electrical signaling to coordinate the heartbeat, we propose that embryonic hearts use mechanical signaling. We model the embryonic heart as mechanically excitable tissue, with cardiac myocytes that are triggered to contract under strain. Such contractions exert strains on nearby cells and induce further contraction, thus propagating the signal through the heart. This simple model captures key features observed in the heartbeat of stiffness-modified embryonic hearts that cannot be explained by standard electrochemical signaling and yields predictions that we confirm with experiments. In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, β-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts—consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats.