Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure

Caimei Zhang, Biyi Chen, Ang Guo, Yanqi Zhu, Jordan D. Miller, Shan Gao, Can Yuan, William Kutschke, Kathy Zimmerman, Robert M. Weiss, Xander H T Wehrens, Jiang Hong, Frances L. Johnson, Luis Fernando Santana, Mark E. Anderson, Long Sheng Song

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Background - : Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether microtubule densification contributes to T-tubule remodeling and excitation-contraction coupling dysfunction in heart disease. METHODS AND RESULTS - : In a mouse model of pressure overload-induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca handling in cultured myocytes by increasing the amplitude of Ca transients and reducing the frequency of Ca sparks. CONCLUSION - : Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation-contraction coupling, and heart failure.

Original languageEnglish (US)
Pages (from-to)1742-1750
Number of pages9
JournalCirculation
Volume129
Issue number17
DOIs
StatePublished - Apr 29 2014
Externally publishedYes

Keywords

  • excitation contraction coupling
  • junctophilin
  • microtubules
  • myocytes, cardiac

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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    Zhang, C., Chen, B., Guo, A., Zhu, Y., Miller, J. D., Gao, S., Yuan, C., Kutschke, W., Zimmerman, K., Weiss, R. M., Wehrens, X. H. T., Hong, J., Johnson, F. L., Santana, L. F., Anderson, M. E., & Song, L. S. (2014). Microtubule-mediated defects in junctophilin-2 trafficking contribute to myocyte transverse-tubule remodeling and Ca2+ handling dysfunction in heart failure. Circulation, 129(17), 1742-1750. https://doi.org/10.1161/CIRCULATIONAHA.113.008452