Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region

Item Type:	Article
Title:	Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region
Creators Name:	Peng, J. and Raddatz, K. and Molkentin, J.D. and Wu, Y. and Labeit, S. and Granzier, H. and Gotthardt, M.
Abstract:	BACKGROUND: Titin is a giant protein crucial for the assembly and elasticity of the sarcomere. Recently, titin has been linked to signal transduction through its kinase domain, which has been proposed to sense mechanical load. We developed a knockout in which expression of M-line-deficient titin can be induced in adult mice and investigated the role of the titin kinase region in cardiac function. METHODS AND RESULTS: Isolated heart experiments revealed that in titin M-line-deficient mice, the contractile response to beta-adrenergic agonists and extracellular calcium is reduced. However, the Ca(2+) sensitivity and cooperativity of activation of skinned cardiac muscle were unchanged. In knockout mice, calcium transients showed a reduced rate of calcium uptake, and expression analysis showed reduced levels of calmodulin, phospholamban, and SERCA2. Ultimately, knockout mice developed cardiac hypertrophy and heart failure, which involves protein kinase C signal transduction but not the mitogen-activated protein kinase pathway. CONCLUSIONS: The titin kinase region emerges as a regulator of contractile function through effects on calcium handling and hypertrophy through protein kinase signal transduction. These novel functions of titin might provide a rationale for future therapeutic approaches to attenuate or reverse symptoms of heart failure.
Keywords:	Cardiac Output, Cardiomyopathy, Cells, Genes, Heart Failure, Mechanics, Animal Models, Calcium, Cardiomegaly, Dobutamine, Knockout Mice, Muscle Proteins, Myocardial Contraction, Protein Kinase C, Protein Kinases, Signal Transduction, Tamoxifen, Ubiquitin-Protein Ligases, Animals, Mice
Source:	Circulation
ISSN:	0009-7322
Publisher:	American Heart Association
Volume:	115
Number:	6
Page Range:	743-751
Date:	13 February 2007
Official Publication:	https://doi.org/10.1161/CIRCULATIONAHA.106.645499
PubMed:	View item in PubMed

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