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Targeting Myocardial Disease

The Muscle Protein Titin Regulates the Contractile Properties of the Heart

Mutations of titin, the largest protein in humans, can lead to myopathies and heart disease. Titin is an important component of the smallest mechanical unit of the heart muscle, the sarcomere. There, titin functions as a molecular spring and ensures that the heart muscle efficiently fills with blood – an important prerequisite that sufficient blood is pumped through the body with every heartbeat, when sarcomeres contract.

Now, for the first time Professor Michael Gotthardt and his colleagues at the MaxDelbrückCenter for Molecular Medicine (MDC) Berlin-Buch, together with researchers at WashingtonState University in Pullman, USA, have shown that titin is directly involved in muscle contraction. The protein receives and processes signals which regulate calcium handling in myocardial cells and thus determines contractile function. Without titin dependent signal transduction, calcium distribution and, thus, contractile function are disturbed.

As the heart is no longer able to pump enough blood throughout the body, the myocardial cells thicken, the heart becomes enlarged, and the sarcomere structure disintegrates. These findings, which have just been published in the American journal Circulation* (DOI:10.1161/CIRCULATIONAHA.106.645499), may explain why people with a mutant (non-functional) form of titin develop heart disease. The researchers hope their findings will contribute to the development of causal therapies for myocardial diseases.

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

Jun Peng, Katy Raddatz, Jeffrey D. Molkentin, Yiming Wu, Siegfried Labeit, Henk Granzier and Michael Gotthardt

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.).

Barbara Bachtler
Press and Public Affairs
Max Delbrück Center for Molecular Medicine (MDC)
Robert-Rössle-Straße 10
13125 Berlin
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33

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