Calcium-dependent titin–thin filament interactions in muscle: observations and theory

Kiisa Nishikawa, Samrat Dutta, Michael DuVall, Brent Nelson, Matthew J. Gage, Jenna A. Monroy

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Gaps in our understanding of muscle mechanics demonstrate that the current model is incomplete. Increasingly, it appears that a role for titin in active muscle contraction might help to fill these gaps. While such a role for titin is increasingly accepted, the underlying molecular mechanisms remain unclear. The goals of this paper are to review recent studies demonstrating Ca2+-dependent interactions between N2A titin and actin in vitro, to explore theoretical predictions of muscle behavior based on this interaction, and to review experimental data related to the predictions. In a recent study, we demonstrated that Ca2+ increases the association constant between N2A titin and F-actin; that Ca2+ increases rupture forces between N2A titin and F-actin; and that Ca2+ and N2A titin reduce sliding velocity of F-actin and reconstituted thin filaments in motility assays. Preliminary data support a role for Ig83, but other Ig domains in the N2A region may also be involved. Two mechanical consequences are inescapable if N2A titin binds to thin filaments in active muscle sarcomeres: (1) the length of titin’s freely extensible I-band should decrease upon muscle activation; and (2) binding between N2A titin and thin filaments should increase titin stiffness in active muscle. Experimental observations demonstrate that these properties characterize wild type muscles, but not muscles from mdm mice with a small deletion in N2A titin, including part of Ig83. Given the new in vitro evidence for Ca2+-dependent binding between N2A titin and actin, it is time for skepticism to give way to further investigation.

Original languageEnglish (US)
Pages (from-to)125-139
Number of pages15
JournalJournal of Muscle Research and Cell Motility
Issue number1
StatePublished - Mar 1 2020


  • Force transmission
  • Muscle activation
  • Muscle mechanics
  • Sarcomere integrity
  • Titin passive stiffness

ASJC Scopus subject areas

  • Physiology
  • Biochemistry
  • Cell Biology


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