Molecular Basis of Passive Stress Relaxation in Human Soleus Fibers: Assessment of the Role of Immunoglobulin-like Domain Unfolding

K. Trombitás, Y. Wu, M. McNabb, M. Greaser, M. S.Z. Kellermayer, S. Labeit, Henk L. Granzier

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Titin (also known as connectin) is the main determinant of physiological levels of passive muscle force. This force is generated by the extensible I-band region of the molecule, which is constructed of the PEVK domain and tandem-immunoglobulin segments comprising serially linked immunoglobulin (Ig)-like domains. It is unresolved whether under physiological conditions Ig domains remain folded and act as "spacers" that set the sarcomere length at which the PEVK extends or whether they contribute to titin's extensibility by unfolding. Here we focused on whether Ig unfolding plays a prominent role in stress relaxation (decay of force at constant length after stretch) using mechanical and immunolabeling studies on relaxed human soleus muscle fibers and Monte Carlo simulations. Simulation experiments using Ig-domain unfolding parameters obtained in earlier single-molecule atomic force microscopy experiments recover the phenomenology of stress relaxation and predict large-scale unfolding in titin during an extended period (>∼20 min) of relaxation. By contrast, immunolabeling experiments failed to demonstrate large-scale unfolding. Thus, under physiological conditions in relaxed human soleus fibers, Ig domains are more stable than predicted by atomic force microscopy experiments. Ig-domain unfolding did not become more pronounced after gelsolin treatment, suggesting that the thin filament is unlikely to significantly contribute to the mechanical stability of the domains. We conclude that in human soleus fibers, Ig unfolding cannot solely explain stress relaxation.

Original languageEnglish (US)
Pages (from-to)3142-3153
Number of pages12
JournalBiophysical Journal
Volume85
Issue number5
DOIs
StatePublished - Nov 2003
Externally publishedYes

ASJC Scopus subject areas

  • Biophysics

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