STIM1-dependent Ca²⁺ microdomains are required for myofilament remodeling and signaling in the heart

In non-excitable cells stromal interaction molecule 1 (STIM1) is a key element in the generation of Ca²⁺ signals that lead to gene expression, migration and cell proliferation. A growing body of literature suggests that STIM1 plays a key role in the development of pathological cardiac hypertrophy. However, the precise mechanisms involving STIM-dependent Ca²⁺ signaling in the heart are not clearly established. Here, we have investigated the STIM1-associated Ca²⁺ signals in cardiomyocytes and their relevance to pathological cardiac remodeling. We show that mice with inducible, cardiac-restricted, ablation of STIM1 exhibited left ventricular reduced contractility, which was corroborated by impaired single cell contractility. The spatial properties of STIM1-dependent Ca 2+ signals determine restricted Ca²⁺ microdomains that regulate myofilament remodeling and activate spatially segregated pro-hypertrophic factors. Indeed, mice lacking STIM1 showed less adverse structural remodeling in response to pressure overload-induced cardiac hypertrophy. These results highlight how STIM1-dependent Ca²⁺ microdomains have a major impact on intracellular Ca²⁺ homeostasis, cytoskeletal remodeling and cellular signaling, even when excitation-contraction coupling is present.