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

Jun Peng, Katy Raddatz, Jeffery D. Molkentin, Yiming Wu, Siegfried Labeit, Hendrikus "Henk" Granzier, Michael Gotthardt

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 β-adrenergic agonists and extracellular calcium is reduced. However, the Ca 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.

Original languageEnglish (US)
Pages (from-to)743-751
Number of pages9
JournalCirculation
Volume115
Issue number6
DOIs
StatePublished - Feb 2007
Externally publishedYes

Fingerprint

Connectin
Myocardial Contraction
Cardiomegaly
Calcium
Signal Transduction
Heart Failure
Knockout Mice
Adrenergic Agonists
Sarcomeres
Elasticity
Calmodulin
Mitogen-Activated Protein Kinases
Protein Kinases
Protein Kinase C
Hypertrophy
Myocardium
Phosphotransferases

Keywords

  • Cardiac output
  • Cardiomyopathy
  • Cells
  • Genes
  • Heart failure
  • Mechanics
  • Models, animal

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region. / Peng, Jun; Raddatz, Katy; Molkentin, Jeffery D.; Wu, Yiming; Labeit, Siegfried; Granzier, Hendrikus "Henk"; Gotthardt, Michael.

In: Circulation, Vol. 115, No. 6, 02.2007, p. 743-751.

Research output: Contribution to journalArticle

Peng, Jun ; Raddatz, Katy ; Molkentin, Jeffery D. ; Wu, Yiming ; Labeit, Siegfried ; Granzier, Hendrikus "Henk" ; Gotthardt, Michael. / Cardiac hypertrophy and reduced contractility in hearts deficient in the titin kinase region. In: Circulation. 2007 ; Vol. 115, No. 6. pp. 743-751.
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