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J. Cell Biol., Volume 146, Number 3, August 9, 1999 631-644
Copyright © 1999 by The Rockefeller University Press.

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

Correspondence to: Wolfgang A. Linke, Physiologisches Institut II, Universität Heidelberg, Im Neuenheimer Feld 326, D-69120 Heidelberg, Germany. Tel:49-6221-544054 Fax:49-6221-544049 E-mail: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


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