© 2000 American Heart Association, Inc.
Cellular Biology |
Differential Expression of Cardiac Titin Isoforms and Modulation of Cellular Stiffness
From the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology (O.C., M.H., M.M., Y.W., K.T., H.G.), Washington State University, Pullman, Wash; the Institut für Anästhesiologie und Operative Intensivmedizin (A.F., T.C., S.L.), Universitätsklinikum, Mannheim, Germany; and European Molecular Biology Laboratory (T.C., S.L.), Heidelberg, Germany.
Correspondence to Henk Granzier, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Wegner Hall 205, Washington State University, Pullman, WA 99164-6520. E-mail granzier{at}wsunix.wsu.edu
Abstract—Extension of the I-band
segment of titin gives rise to part of the diastolic force
of cardiac muscle. Previous studies of human cardiac titin transcripts
suggested a series of differential splicing events in the I-band
segment of titin leading to the so-called N2A and N2B isoform
transcripts. Here we investigated titin expression at the protein level
in a wide range of mammalian species. Results indicate that the
myocardium coexpresses 2 distinct titin isoforms: a smaller
isoform containing the N2B element only (N2B titin) and a larger
isoform with both the N2B and N2A elements (N2BA titin). The expression
ratio of large N2BA to small N2B titin isoforms was found to vary
greatly in different species; eg, in the left ventricle the ratio is
0.05 in mouse and 1.5 in pig. Differences in the expression ratio
were also found between atria and ventricles and between different
layers of the ventricular wall.
Immunofluorescence experiments with
isoform-specific antibodies suggest that coexpression of these isoforms
takes place at the single-myocyte level. The diastolic
properties of single cardiac myocytes isolated from various species
expressing high levels of the small (rat and mouse) or large (pig)
titin isoform were studied. On average, pig myocytes are significantly
less stiff than mouse and rat myocytes. Gel analysis indicates
that this result cannot be explained by varying amounts of titin in
mouse and pig myocardium. Rather, low stiffness of pig
myocytes can be explained by its high expression level of the large
isoform: the longer extensible region of this isoform results in a
lower fractional extension for a given sarcomere length and hence a
lower force. Implications of our findings to cardiac function are
discussed.
Key Words: compliance • passive tension • diastolic force • mechanical properties • myocyte • connectin
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