Bridging Integrator 1 (BIN1)-Induced T-Tubule Formation in Cardiomyocytes

The T-tubule system is a branching network of membrane invaginations essential for efficient Ca2+-induced Ca2+ release in myocytes. Significant remodeling of this system has been observed during heart failure (HF), resulting in delayed Ca2+ release at sites lacking T-tubules. Despite its considerable role in HF aetiology, the signaling mechanisms behind T-tubule remodeling remain largely unknown. Bridging integrator 1 (BIN1) has recently drawn considerable interest due to its altered expression during HF and ability to tubulate membranes. In rats examined 6 weeks following myocardial infarction, BIN1 transcription was significantly elevated in animals with compensated or end-stage HF, compared to SHAM operated controls. Although overall T-tubule density was unchanged, confocal imaging of isolated cells stained with di-8-ANEPPS confirmed that the transverse pattern of T-tubules was lost in failing cardiomyocytes, as indicated by reduced peak power in fast Fourier transforms. Interestingly, between-peak power was increased, consistent with the increased fraction of longitudinal tubules visible in failing cardiomyocytes. The role of BIN1 in T-tubule growth was investigated using HL-1 cells, a differentiated murine cardiac cell line lacking both intrinsic BIN1 and T-tubules. When transfected with hBIN1, HL-1 cells developed BIN1-positive invaginations as early as 12 hours following transfection. Whereas BIN1 transcript and protein levels rapidly rose to a peak 24 hours following transfection, BIN1-generated tubules gradually increased in density up until 48 hours after transfection. Additionally, early Ca2+ release at sites containing BIN1-positive tubules indicated that these structures improve Ca2+ release synchrony across the cell. We propose that BIN1 is a crucial regulator of T-tubule development in both healthy and failing cardiomyocytes. In the setting of heart failure, increased BIN1 expression may promote growth of longitudinal tubules that compensate for loss of transverse elements, thereby improving calcium homeostasis in this disease.