Imperial College London
Alternate

Emeritus ProfessorMichaelSchneider

Faculty of Medicine, National Heart & Lung Institute

Emeritus Professor in Cardiology
 
 
 
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Contact

 

+44 (0)013 34621727m.d.schneider Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Ibrahim:2013:hmg/dds434,
author = {Ibrahim, M and Siedlecka, U and Buyandelger, B and Harada, M and Rao, C and Moshkov, A and Bhargava, A and Schneider, M and Yacoub, MH and Gorelik, J and Knoll, R and Terracciano, CM},
doi = {hmg/dds434},
journal = {Hum Mol Genet},
pages = {372--383},
title = {A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart},
url = {http://dx.doi.org/10.1093/hmg/dds434},
volume = {22},
year = {2013}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The transverse (t)-tubule system plays an essential role in healthy and diseased heart muscle, particularly in Ca(2+)-induced Ca(2+) release (CICR), and its structural disruption is an early event in heart failure. Both mechanical overload and unloading alter t-tubule structure, but the mechanisms mediating the normally tight regulation of the t-tubules in response to load variation are poorly understood. Telethonin (Tcap) is a stretch-sensitive Z-disc protein that binds to proteins in the t-tubule membrane. To assess its role in regulating t-tubule structure and function, we used Tcap knockout (KO) mice and investigated cardiomyocyte t-tubule and cell structure and CICR over time and following mechanical overload. In cardiomyocytes from 3-month-old KO (3mKO), there were isolated t-tubule defects and Ca(2+) transient dysynchrony without whole heart and cellular dysfunction. Ca(2+) spark frequency more than doubled in 3mKO. At 8 months of age (8mKO), cardiomyocytes showed progressive loss of t-tubules and remodelling of the cell surface, with prolonged and dysynchronous Ca(2+) transients. Ca(2+) spark frequency was elevated and the L-type Ca(2+) channel was depressed at 8 months only. After mechanical overload obtained by aortic banding constriction, the Ca(2+) transient was prolonged in both wild type and KO. Mechanical overload increased the Ca(2+) spark frequency in KO alone, where there was also significantly more t-tubule loss, with a greater deterioration in t-tubule regularity. In conjunction, Tcap KO showed severe loss of cell surface ultrastructure. These data suggest that Tcap is a critical, load-sensitive regulator of t-tubule structure and function.
AU  - Ibrahim,M
AU  - Siedlecka,U
AU  - Buyandelger,B
AU  - Harada,M
AU  - Rao,C
AU  - Moshkov,A
AU  - Bhargava,A
AU  - Schneider,M
AU  - Yacoub,MH
AU  - Gorelik,J
AU  - Knoll,R
AU  - Terracciano,CM
DO  - hmg/dds434
EP  - 383
PY  - 2013///
SN  - 1460-2083
SP  - 372
TI  - A critical role for Telethonin in regulating t-tubule structure and function in the mammalian heart
T2  - Hum Mol Genet
UR  - http://dx.doi.org/10.1093/hmg/dds434
UR  - http://www.ncbi.nlm.nih.gov/pubmed/23100327
VL  - 22
ER  -
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