Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure

BIYI CHEN; CAIMEI ZHANG; Frances L JOHNSON; Xander H. T WEHRENS; Long-Sheng SONG; William KUTSCHKE; JIANG HONG; Kathy ZIMMERMAN; Robert M WEISS; Luis F SANTANA; Mark E ANDERSON; ANG GUO; YANQI ZHU; Jordan D MILLER; SHAN GAO; CAN YUAN

doi:10.1161/CIRCULATIONAHA.113.008452

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Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure

Journal article

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Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure

BIYI CHEN, CAIMEI ZHANG, Frances L JOHNSON, Xander H. T WEHRENS, Long-Sheng SONG, William KUTSCHKE, JIANG HONG, Kathy ZIMMERMAN, Robert M WEISS, Luis F SANTANA, …

Circulation (New York, N.Y.), Vol.129(17), pp.1742-1750

2014

DOI: 10.1161/CIRCULATIONAHA.113.008452

PMID: 24519927

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https://doi.org/10.1161/CIRCULATIONAHA.113.008452View

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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 Ca2+ handling in cultured myocytes by increasing the amplitude of Ca2+ transients and reducing the frequency of Ca2+ 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.

Heart

Cardiology. Vascular system

Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous

Biological and medical sciences

Medical sciences

Heart failure, cardiogenic pulmonary edema, cardiac enlargement

Blood and lymphatic vessels

Details

Title: Subtitle: Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca2+ Handling Dysfunction in Heart Failure
Creators: BIYI CHEN - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
CAIMEI ZHANG - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Frances L JOHNSON - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Xander H. T WEHRENS - Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, United States
Long-Sheng SONG - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
William KUTSCHKE - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
JIANG HONG - Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China
Kathy ZIMMERMAN - Department of Veterans Affairs Medical Center, Iowa City, IA, United States
Robert M WEISS - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Luis F SANTANA - Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, United States
Mark E ANDERSON - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
ANG GUO - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
YANQI ZHU - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
Jordan D MILLER - Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN, United States
SHAN GAO - Division of Cardiovascular Medicine, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, IA, United States
CAN YUAN - Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, WA, United States
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.129(17), pp.1742-1750
DOI: 10.1161/CIRCULATIONAHA.113.008452
PMID: 24519927
NLM abbreviation: Circulation
ISSN: 0009-7322
eISSN: 1524-4539
Publisher: Lippincott Williams & Wilkins
Language: English
Date published: 2014
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984094504902771

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