Mechanical response and disruption of the T-tubule microenvironment in the mammalian myocardium: a structural basis for cellular resilience

With every heartbeat, cardiomyocytes are exposed to mechanical stress, and yet they effectively retain a highly ordered internal structure, while flexibly adapting to their environment, a capacity referred to as resilience. Under physiological conditions, the cardiomyocytes in adult mammals are characterized by a limited proliferative capacity, thereby necessitating the maintenance of cellular homeostasis via structural and functional plasticity. In this review, we focus on the transverse-tubule (T-tubule) membrane as a key structural element underlying this cellular resilience. Traditionally recognized as a pivotal site associated with calcium signaling during excitation-contraction coupling, it has now been established that T-tubule membranes are more than merely static anatomical features. The findings of recent studies have revealed that during contraction, these membranes undergo passive deformation and are actively remodeled in response to mechanical load, demonstrating a capacity for structural resilience. Furthermore, T-tubules contribute to a unique membranous microenvironment deep within the cell, facilitating the spatiotemporal regulation of calcium signaling and enabling rapid responses to external stimuli. Importantly, structural disorganization of the T-tubule network is frequently observed prior to the onset of heart failure, thus highlighting its essential role in maintaining cardiomyocyte function. By examining the dynamic interplay between T-tubule structure and function, in this review, we provide new insights into the mechanisms underlying cardiomyocyte resilience and identify potential therapeutic targets for preserving structural homeostasis in cardiac disease.