Human BIN1 isoforms grow, maintain, and regenerate excitation-contraction couplons in adult rat and human stem cell-derived cardiomyocytes
Guo J, Tian Q, Barth M, Xian W, Ruppenthal S, Schaefers HJ, Chen Z, Moretti A, Laugwitz KL, Lipp P (2022)
Publication Type: Journal article
Publication year: 2022
Journal
Book Volume: 118
Pages Range: 1479-1491
Journal Issue: 6
DOI: 10.1093/cvr/cvab195
Abstract
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.
Involved external institutions
Germany (DE)How to cite
APA:
Guo, J., Tian, Q., Barth, M., Xian, W., Ruppenthal, S., Schaefers, H.-J.,... Lipp, P. (2022). Human BIN1 isoforms grow, maintain, and regenerate excitation-contraction couplons in adult rat and human stem cell-derived cardiomyocytes. Cardiovascular Research, 118(6), 1479-1491. https://doi.org/10.1093/cvr/cvab195
MLA:
Guo, Jia, et al. "Human BIN1 isoforms grow, maintain, and regenerate excitation-contraction couplons in adult rat and human stem cell-derived cardiomyocytes." Cardiovascular Research 118.6 (2022): 1479-1491.
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