title: Mechanical signaling coordinates the embryonic heartbeat.
abstract: 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.
authors.affiliation: Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kevin K
authors.initials: KK
authors.lastname: Chiou
authors.affiliation: Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jason W
authors.initials: JW
authors.lastname: Rocks
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Christina Yingxian
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Sangkyun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Applied Physics, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands.
authors.forename: Koen E
authors.initials: KE
authors.lastname: Merkus
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Anjali
authors.initials: A
authors.lastname: Rajaratnam
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Patrick
authors.initials: P
authors.lastname: Robison
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Manorama
authors.initials: M
authors.lastname: Tewari
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Kenneth
authors.initials: K
authors.lastname: Vogel
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Stephanie F
authors.initials: SF
authors.lastname: Majkut
authors.affiliation: Department of Physiology, Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104;
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Prosser
authors.affiliation: Molecular and Cell Biophysics Laboratory, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Discher
authors.affiliation: Department of Physics and Astronomy, University of Pennsylvania, Philadelphia, PA 19104; ajliu@physics.upenn.edu.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Liu
mesh_terms: D000818:Animals; D002642:Chick Embryo; D017629:Gap Junctions / Q000502:physiology; D006321:Heart / Q000196:embryology*; D006339:Heart Rate; D008954:Models, Biological; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology
keywords: cardiac development; excitable media; heartbeat; mechanotransduction; reaction–diffusion