Rules of life at the interface of calcium signaling and mechanobiology

Living systems process a broad range of internal and external stimuli, respond to environmental constraints, and adapt to various conditions through tight coordination between signaling networks and cellular mechanics. Among these, calcium signaling and cytoskeletal regulation form an essential interplay that spans multiple scales of biological organization-from ion-protein interactions to intercellular communication and tissue-level behaviors. Calcium ions (Ca²⁺) act as universal messengers, integrating a wide range of cellular signaling inputs to modulate a broad range of cellular structures and functions through the spatiotemporal dynamics of their concentration changes. Ca²⁺ signals follow conserved principles, despite their diverse roles, that define regulatory "Rules of Life" (RoLs)-generalized mechanisms that operate across biological contexts. This review focuses on how Ca²⁺ regulates and is regulated by cytoskeletal dynamics, with a particular emphasis on computational modeling for predictive simulations. As key examples, we highlight three specific RoLs: (1) Ca²⁺ dynamics facilitate cytoskeletal reorganization following stress and damage, (2) Ca²⁺ regulates actin dynamics to control synapse processes supporting both synapse formation and exocytosis, and (3) reciprocal coupling of spatiotemporal Ca²⁺ signaling and cellular dynamics defines distinct cellular roles in emergent multicellular behavior. Finally, we outline future directions toward developing multimodal computational simulations for identifying new RoLs, integrating them into multi-scale computational frameworks, and applications in bioengineering, pharmacology, and regenerative medicine.