Henk L. Granzier

Professor of Molecular & Cellular Biology
Allan and Alfie Norville Endowed Chair, Molecular Cardiovascular Research Program
Ph.D., University of Washington

Role of the filamentous proteins titin and nebulin in function of normal and diseased muscle.

Research Interests

We study the mechanisms whereby the giant filamentous protein titin (the largest protein known) influence muscle structure and function. Our lab has shown that titin functions as a molecular spring that mediates acute responses to changing pathophysiological states of the heart. We also study the role of titin in cardiac disease, using mouse models with specific modifications in the titin gene, including deciphering the mechanisms that are responsible for gender differences in diastolic dysfunction. An additional focus of our lab is on nebulin, a major muscle protein that causes a severe skeletal muscle disease in humans. Based on our previous work, we hypothesize that nebulin is a determinant of calcium sensitivity of contractile force. To test this and other concepts we use a nebulin knockout approach in the mouse. Our research is multi-faceted, and uses cutting-edge techniques at levels ranging across the single molecule, single cell, muscle, and the intact heart. Our research group is diverse and has brought together individuals from several continents with expertise ranging from Physics and Chemistry to Cell Biology and Physiology.

Select Publications

Granzier, H.L., M. Radke, J. Royal, Y. Wu, T.C. Irving, M. Gotthardt, and S. Labeit. 2007. Functional genomics of chicken, mouse, and human titin supports splice diversity as an important mechanism for regulating biomechanics of striated muscle. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology (Epub-ahead of print).

Radke, M.H., J. Peng, Y. Wu, M. McNabb, O.L. Nelson, H. Granzier, and M. Gotthardt. 2007. Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy. Proceedings of the National Academy of Sciences U.S.A. 104: 3444-3449.

Witt, C.C., C. Burkart, D. Labeit, M. McNabb, Y Wu, H. Granzier, and S. Labeit.  2006. Nebulin regulates thin filament length, contractility, and Z-disk structure in vivo. The EMBO Journal 25: 3843-3855.

Fukuda, N., Y. Wu, P. Nair, and H.L. Granzier. 2005. Phosphorylation of titin modulates passive stiffness of cardiac muscle in a titin isoform-dependent manner. Journal of General Physiology 125: 257-271.

Nagueh, S.F., G. Shah, Y. Wu, G. Torre-Amione, N.M. King, S. Lahmers, C.C. Witt, K. Becker, S. Labeit, and H.L. Granzier. 2004. Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy. Circulation 110: 155-162.

Granzier, H.L., and S. Labeit. 2004. The giant protein titin: a major player in myocardial mechanics, signaling, and disease. Circulation Research 94: 284-295.

Labeit, D., K. Watanabe, C. Witt, H. Fujita, Y. Wu, S. Lahmers, T. Funck, S. Labeit, H. Granzier. 2003. Calcium-dependent molecular spring elements in the giant protein titin. Proceedings of the National Academy of Sciences U.S.A. 100: 13716-13721.

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