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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy
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*Department of Neuromuscular and Cardiovascular Cell Biology, Max-Delbrück-Center for Molecular Medicine, D-13122 Berlin-Buch, Germany; and Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, and Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA 99164
Edited by Christine E. Seidman, Harvard Medical School, Boston, MA, and approved December 20, 2006 (received for review September 27, 2006)
Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and 
B-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process.
cardiac muscle | hypertrophy | mechanics | cardiology | disease
The authors declare no conflict of interest.
This article is a PNAS direct submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0608543104/DC1.
To whom correspondence should be addressed at: Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Wegner Hall, Room 205, Pullman, WA 99164-6520 or Max-Delbrück-Center for Molecular Medicine Berlin-Buch, Robert Rössle Strasse 10, 13122 Berlin, Germany. E-mail: gotthard{at}vetmed.wsu.edu or gotthardt{at}mdc-berlin.de
© 2007 by The National Academy of Sciences of the USA
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