Imperial College London

ProfessorMichaelSchneider

Faculty of MedicineNational Heart & Lung Institute

Chair in Cardiology
 
 
 
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Contact

 

+44 (0)20 7594 3027m.d.schneider Website

 
 
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Assistant

 

Miss Cassie Tarquini +44 (0)20 7594 3020

 
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Location

 

336ICTEM 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}
}

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 -