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The role of
the elastic protein titin in the function of normal and diseased muscle.
Titin is a recently discovered filamentous protein that constitutes ~10% of
the total muscle protein mass. It is the largest protein known to date. A
single polypeptide contains ~30,000 amino acids, and spans the distance
between the Z- and M-lines of the vertebrate muscle sarcomere. To
investigate the function of this protein, we use a combination of
mechanical, biochemical, and immunological techniques at both the molecular
and cellular level. Examples of ongoing research: (1) Isolation of single
titin molecules and measurement of their force-length relation using
laser-tweezers to establish whether the elastic properties of titin underlie
the passive force of muscle. (2) Investigation of effect of genetically
engineered titin fragments on sliding of thin and thick filaments (these
filaments are responsible for muscle force and muscle shortening) using
recently developed in vitro motility techniques. (3) Role of titin in heart
disease. This work investigates the role(s) of titin in the altered passive
properties of the diseased heart. Currently we investigate the role of titin
in dilated cardiomyopathy (DCM), which is heart disease characterized by
ventricular enlargement and altered passive properties.
The recent
discovery of the major muscle protein titin and the introduction of many new
molecular techniques makes for an exciting future in this field and creates
opportunities for participation with the endeavors in my laboratory. My
research group is diverse and has brought together individuals from several
continents with expertise ranging from physics and chemistry to cell biology
and medicine.
Biographical Information
Henk L.
Granzier, Associate Professor, received a B.S. in biology (1980) and a
Masters in biology (1983) from the Agricultural University of the Netherlands at
Wageningen. He received a Fulbright Fellowship for studies at the University of Washington and obtained a Ph.D. in
bioengineering in 1988. He then moved to the University of Texas at Austin where he was a Neuromuscular Disease
Research Fellow of the Muscular Dystrophy Association from 1988-1990 and
a Research Associate from 1990-1992. He joined the VCAPP faculty in
1993. He is an Established Investigator of the American heart
association and is a member of multiple grant review panels.
Most Recent Publications
Fukuda N, Wu Y, Nair P, and
Granzier H. 2005. Phosphorylation of titin modulates
passive stiffness of cardiac muscle in a titin isoform-dependent
manner. Journal of General Physiology. 125(3):257-71. (Article
received an Editorial: Journal of General Physiology, Mar;125(3):249-52)
Campbell KB, Wu Y,
Simpson AM, Kirkpatrick RD, Shroff SG, Granzier HL, Slinker BK.
Dynamic Myocardial Contractile
Parameters from Left Ventricular Pressure/Volume Measurements.
American Journal of Physiology, Heart and
Circulation; (on line December 10,
2004). 2005
Jul;289(1):H114-30
Witt SH,
Witt CC, Granzier H, Labeit S.
2005. MURF-1 and
MURF2 target a specific subset of myofibrillar proteins redundantly:
Towards understanding MURF-family dependent muscle turnover. Journal
of Molecular Biology, 350,713-722.
Nagy A, Grama
L, Huber T, Bianco P, Trombitás K, Granzier HL, Kellermayer MSZ. 2005. Hierarchical extensibility in the PEVK domain
of skeletal-muscle titin. Biophysical Journal, 2005 Jul;89(1):329-36. Epub 2005 Apr 22.
Coen AC, Ottenheijm L, Heunks MA, Hafmans T, Peter FM, van der Ven, Benoist
C, Zhou H, Labeit S, Granzier HL, Dekhuijzen PNR. Titin and passive
tension in diaphragm dysfunction of chronic obstructive pulmonary
disease patients. American Journal of Respiratory and Critical Care
Medicine. 2005 Dec 9; [Epub ahead of print]
(Selected for cover photo of Journal.)
Granzier H,
Labeit S. 2005. Titin and its
associated proteins: the third myofilament system of the sarcomere.
Adv Protein Chem.
71:89-119
Granzier H,
Wu Y, Labeit S, LeWinter M.
2005. Titin: physiological function and role in cardiomyopathy and
failure. Heart Fail Rev. Sep;10(3):211-23.
Selected Earlier Publications (from >100)
Fukuda N, Wu Y,
Nair, P, Granzier H. 2005. Phosphorylation of
titin modulates passive stiffness of cardiac muscle in a titin
isoform-dependent manner. Journal of General Physiology.
125(3):257-71. (Article received an Editorial: Journal of General
Physiology, Mar;125(3):249-52)
Campbell
KB, Wu Y, Simpson AM, Kirkpatrick RD, Shroff SG, Granzier HL,
Slinker BK.
Dynamic Myocardial
Contractile Parameters from Left Ventricular Pressure/Volume
Measurements. American Journal of Physiology, Heart and
Circulation; (on line December 10, 2004). 2005
Jul;289(1):H114-30
Lahmers SM,
Wu Y, DR,
Labeit S, Granzier HL.
Developmental control of titin
isoform expression and passive stiffness in fetal and neonatal
myocardium. Circulation Research: Mar
5;94(4):505-13. Epub 2004 Jan 05. (Article received an Editorial:
Circ Res. 2004 Apr 16;94(7):860-2.)
Coen AC,
Ottenheijm L, Heunks MA, Hafmans T, Peter FM, van der Ven, Benoist
C, Zhou H, Labeit S, Granzier HL, and Dekhuijzen PNR. Titin
and passive tension in diaphragm dysfunction of chronic obstructive
pulmonary disease patients. American Journal of Respiratory and
Critical Care Medicine. 2005 Dec 9; [Epub ahead of print]
(Selected for cover photo of Journal.)
Nagueh SF, Shah G, Wu Y, Torre-Amione G, King N, Lahmers
S, Witt CC, Becker K, Labeit S,
Granzier H. 2004 Altered titin expression,
myocardial stiffness, and left ventricular function in patients with
dilated cardiomyopathy. Circulation, 110:155-162. (Article
received an Editorial: Circulation 110(2):109-111)
Granzier H,
Wu Y, Labeit S, LeWinter M.
2005. Titin:
physiological function and role in cardiomyopathy and failure.
Heart Fail Rev. Sep;10(3):211-23.
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