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(Circulation. 2007;115:743-751.)
© 2007 American Heart Association, Inc.

Molecular Cardiology

Cardiac Hypertrophy and Reduced Contractility in Hearts Deficient in the Titin Kinase Region

Jun Peng, MD, PhD; Katy Raddatz, MS; Jeffery D. Molkentin, PhD; Yiming Wu, MD, PhD; Siegfried Labeit, MD; Henk Granzier, PhD; Michael Gotthardt, MD

From the Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman (J.P, Y.W., H.G., M.G.); Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück Center for Molecular Medicine, Berlin, Germany (K.R., M.G.); Division of Molecular Cardiovascular Biology, Department of Pediatrics, Children’s Hospital Medical Center, Cincinnati, Ohio (J.M.); and Department of Anesthesiology, Mannheim University, Mannheim, Germany (S.L.).

Correspondence to Michael Gotthardt, VCAPP, Washington State University, Wegner Hall, Room 205, Pullman, WA 99164–6520 (e-mail gotthard{at}vetmed.wsu.edu); or Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Robert Rössle Str 10, 13125 Berlin, Germany (e-mail gotthardt@mdc-berlin.de).

Received June 13, 2006; accepted November 20, 2006.

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 ß-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.

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