Key result
Viral transduction of human BIN1 splice variants, especially those with a PI motif, induced de novo generation of functional T-tubules and enhanced calcium handling in cardiomyocytes.
Why the study?
T-tubule disarray is a hallmark of cardiac diseases, and the role of human BIN1 splice variants in maintaining and regenerating excitation-contraction coupling required investigation.
Human BIN1 splice variants, particularly those with a PI-motif, are essential for generating and maintaining functional T-tubules and enhancing calcium handling in ventricular myocytes.
Hypothesis-generating for BIN1 gene therapy in heart failure; human studies needed before clinical translation.
AIMS: In ventricular myocytes, transverse-tubules (T-tubules) are instrumental for excitation-contraction (EC)coupling and their disarray is a hallmark of cardiac diseases. BIN1 is a key contributor to their biogenesis. Our study set out to investigate the role of human BIN1 splice variants in the maintenance and regeneration of EC-coupling in rat adult ventricular myocytes and human-induced pluripotent stem cell-derived cardiac myocytes (hiPS-CMs). METHODS AND RESULTS: In heart samples from healthy human donors expression patterns of five BIN1 splice variants were identified. Following viral transduction of human BIN1 splice variants in cellular models of T-tubular disarray, we employed high-speed confocal calcium imaging and CaCLEAN analysis to identify functional EC-coupling sites (couplons) and T-tubular architecture. Adult rat ventricular myocytes were used to investigate the regeneration after loss and maintenance of EC-coupling while we studied the enhancement of EC-coupling in hiPS-CMs. All five human BIN1 splice variants induced de-novo generation of T-tubules in both cell types. Isoforms with the phosphoinositide-binding motif (PI) were most potent in maintenance and regeneration of T-tubules and functional EC-coupling in adult rat myocytes. In hiPSC-CMs, BIN1 variants with PI-motif-induced de novo generation of T-tubules, functional couplons and enhanced calcium handling. CONCLUSION: BIN1 is essential for the maintenance, regeneration, and de novo generation of functional T-tubules. Isoforms with PI-motifs appeared as particulalrly potent. These T-tubules trigger the development of functional couplons resulting in enhanced calcium handling.
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Guo et al. (2021) studied T-tubular disarray. Human BIN1 splice variants was evaluated on Generation, maintenance, and regeneration of T-tubules and functional EC-coupling. Viral transduction of human BIN1 splice variants, especially those with a PI motif, induced de novo generation of functional T-tubules and enhanced calcium handling in cardiomyocytes.
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