A myofibre model for the study of uterine excitation-contraction dynamics

Abstract

As the uterus remodels in preparation for delivery, the excitability and contractility of the uterine smooth muscle layer, the myometrium, increase drastically. But when remodelling proceeds abnormally it can contribute to preterm birth, slow progress of labour, and failure to initiate labour. Remodelling increases intercellular coupling and cellular excitability, which are the main targets of pharmaceutical treatments for uterine contraction disorders. However, the way in which electrical propagation and force development depend on intercellular coupling and cellular excitability is not fully understood. Using a computational myofibre model we study the dependency of electrical propagation and force development on intercellular coupling and cellular excitability. This model reveals that intercellular coupling determines the conduction velocity. Moreover, our model shows that intercellular coupling alone does not regulate force development. Further, cellular excitability controls whether conduction across the cells is blocked. Lastly, our model describes how cellular excitability regulates force development. Our results bridge cellular factors, targeted by drugs to regulate uterine contractions, and tissue level electromechanical properties, which are responsible for delivery. They are a step forward towards understanding uterine excitation-contraction dynamics and developing safer and more efficient pharmaceutical treatments for uterine contraction disorders.

Does Precision-Based Medicine Hold the Promise of a New Approach to Predicting and Treating Spontaneous Preterm Birth?

“…An example of this is Goldsztejn and Nehorai's computational myofiber model, which studied both electropropagation and uterine force development on intracellular coupling and cellular excitability. Their work described the complexity of electrochemical pressure dynamics in the initiation of contractions [148].…”

“…This study highlights the potential of computational drug repositioning to discover compounds that could be effective in preventing PTL. Goldsztejn and Nehorai, 2020 [148] Computational/in vitro Experimental…”

Physiology and Pathology of Contractility of the Myometrium

“…Thus, while under normal circumstances the resting potential is -60 to -90 mV, this can be differentiated by hormonal factors (2). The electrical stimulating action is referred to as "electromechanical coupling" (10).…”

“…Subsequently, after the gradual loss of Na + ions' ability to easily penetrate the cell, the Na + and K + pumps, with the help of ATP and the ATPase enzyme, restore the concentration of ions to their resting state, thereby, restoring the resting potential (3). This "electrical" stimulation process leads to muscle cell contraction and is referred to as "electromechanical coupling" (10). A key precondition, of course, for this contraction to occur, is to ensure the ability of the cell to consume energy (i.e., ATP and phosphocreatine), so as to allow a corresponding reaction in the contraction proteins, actin and myosin.…”