Imperial College London
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DrPetrVikhorev

Faculty of Engineering, Department of Bioengineering

Research Associate in Biophysics of Auditory Hair Cells
 
 
 
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p.vikhorev

 
 
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Location

 

B124Bessemer BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Vikhorev:2022:cvr/cvaa316,
author = {Vikhorev, P and Vikhoreva, N and Yeung, W and Li, A and Sean, L and dos, Remedios C and Blair, C and Maya, G and Campbell, K and Yacoub, M and de, Tombe P and Marston, S},
doi = {cvr/cvaa316},
journal = {Cardiovascular Research},
pages = {241--253},
title = {Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation},
url = {http://dx.doi.org/10.1093/cvr/cvaa316},
volume = {118},
year = {2022}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Aims Dilated cardiomyopathy (DCM) is associated with mutations in many genes encoding sarcomere proteins. Truncating mutations in the titin gene TTN are the most frequent. Proteomic and functional characterizations are required to elucidate the origin of the disease and the pathogenic mechanisms of TTN-truncating variants.Methods and results We isolated myofibrils from DCM hearts carrying truncating TTN mutations and measured the Ca2+ sensitivity of force and its length dependence. Simultaneous measurement of force and adenosine triphosphate (ATP) consumption in skinned cardiomyocytes was also performed. Phosphorylation levels of troponin I (TnI) and myosin binding protein-C (MyBP-C) were manipulated using protein kinase A and λ phosphatase. mRNA sequencing was employed to overview gene expression profiles. We found that Ca2+ sensitivity of myofibrils carrying TTN mutations was significantly higher than in myofibrils from donor hearts. The length dependence of the Ca2+ sensitivity was absent in DCM myofibrils with TTN-truncating variants. No significant difference was found in the expression level of TTN mRNA between the DCM and donor groups. TTN exon usage and splicing were also similar. However, we identified down-regulation of genes encoding Z-disk proteins, while the atrial-specific regulatory myosin light chain gene, MYL7, was up-regulated in DCM patients with TTN-truncating variants.Conclusion Titin-truncating mutations lead to decreased length-dependent activation and increased elasticity of myofibrils. Phosphorylation levels of TnI and MyBP-C seen in the left ventricles are essential for the length-dependent changes in Ca2+ sensitivity in healthy donors, but they are reduced in DCM patients with TTN-truncating variants. A decrease in expression of Z-disk proteins may explain the observed decrease in myofibril passive stiffness and length-dependent activation.
AU  - Vikhorev,P
AU  - Vikhoreva,N
AU  - Yeung,W
AU  - Li,A
AU  - Sean,L
AU  - dos,Remedios C
AU  - Blair,C
AU  - Maya,G
AU  - Campbell,K
AU  - Yacoub,M
AU  - de,Tombe P
AU  - Marston,S
DO  - cvr/cvaa316
EP  - 253
PY  - 2022///
SN  - 0008-6363
SP  - 241
TI  - Titin-truncating mutations associated with dilated cardiomyopathy alter length-dependent activation and its modulation via phosphorylation
T2  - Cardiovascular Research
UR  - http://dx.doi.org/10.1093/cvr/cvaa316
UR  - http://hdl.handle.net/10044/1/84789
VL  - 118
ER  -
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