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


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 Ca2+ 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.
Peng
Jun
J
Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, WA 99164-6520, USA.
Raddatz
Katy
K
Molkentin
Jeffery D
JD
Wu
Yiming
Y
Labeit
Siegfried
S
Granzier
Henk
H
Gotthardt
Michael
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000209:etiology*; D064211:Connectin; D004280:Dobutamine / Q000494:pharmacology; D006333:Heart Failure / Q000209:etiology; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000502:physiology*; D009200:Myocardial Contraction; D011493:Protein Kinase C / Q000502:physiology; D011494:Protein Kinases / Q000502:physiology*; D015398:Signal Transduction; D013629:Tamoxifen / Q000494:pharmacology; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000502:physiology
D064211:Connectin; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D013629:Tamoxifen; D004280:Dobutamine; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases; D011493:Protein Kinase C; D002118:Calcium