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© The Rockefeller University Press, 0021-9525/1999//631 $5.00
The Journal of Cell Biology, Volume 146, Number 3, , 1999 631-644

Original Article

I-Band Titin in Cardiac Muscle Is a Three-Element Molecular Spring and Is Critical for Maintaining Thin Filament Structure



Wolfgang A. Linkea, Diane E. Rudyb, Thomas Centnerc, Mathias Gautelc,d, Christian Wittc,e, Siegfried Labeitc,e, and Carol C. Gregoriob,f

a Physiologisches Institut II, Universität Heidelberg, D-69120 Heidelberg, Germany
b Department of Cell Biology and Anatomy, University of Arizona, Tucson, Arizona 85724
c European Molecular Biology Laboratory, D-69012 Heidelberg, Germany
d Max-Planck-Institut für molekulare Physiologie, D-44202 Dortmund, Germany
e Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, D-68167 Mannheim, Germany
f Department of Molecular and Cellular Biology, University of Arizona, Tucson, Arizona 85721
Physiologisches Institut II, Universität Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany.49-6221-54404949-6221-544054

wolfgang.linke{at}urz.uni-heidelberg.de

In cardiac muscle, the giant protein titin exists in different length isoforms expressed in the molecule's I-band region. Both isoforms, termed N2-A and N2-B, comprise stretches of Ig-like modules separated by the PEVK domain. Central I-band titin also contains isoform-specific Ig-motifs and nonmodular sequences, notably a longer insertion in N2-B. We investigated the elastic behavior of the I-band isoforms by using single-myofibril mechanics, immunofluorescence microscopy, and immunoelectron microscopy of rabbit cardiac sarcomeres stained with sequence-assigned antibodies. Moreover, we overexpressed constructs from the N2-B region in chick cardiac cells to search for possible structural properties of this cardiac-specific segment.

We found that cardiac titin contains three distinct elastic elements: poly-Ig regions, the PEVK domain, and the N2-B sequence insertion, which extends ~60 nm at high physiological stretch. Recruitment of all three elements allows cardiac titin to extend fully reversibly at physiological sarcomere lengths, without the need to unfold Ig domains. Overexpressing the entire N2-B region or its NH2 terminus in cardiac myocytes greatly disrupted thin filament, but not thick filament structure. Our results strongly suggest that the NH2-terminal N2-B domains are necessary to stabilize thin filament integrity. N2-B–titin emerges as a unique region critical for both reversible extensibility and structural maintenance of cardiac myofibrils.

Key Words: heart muscle • connectin • elasticity • transfection • sarcomere

© 1999 The Rockefeller University Press

1.used in this paper: GFP, green fluorescence protein; MyBP-C, myosin-binding protein C; SL, sarcomere length; WLC, worm-like chain


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