Is titin a 'winding filament'? A new twist on muscle contraction

Kiisa C. Nishikawa, Jenna A. Monroy, Theodore E. Uyeno, Sang Hoon Yeo, Dinesh K. Pai, Stan L. Lindstedt

Research output: Contribution to journalArticlepeer-review

167 Scopus citations


Recent studies have demonstrated a role for the elastic protein titin in active muscle, but the mechanisms by which titin plays this role remain to be elucidated. In active muscle, Ca2+-binding has been shown to increase titin stiffness, but the observed increase is too small to explain the increased stiffness of parallel elastic elements upon muscle activation. We propose a 'winding filament' mechanism for titin's role in active muscle. First, we hypothesize that Ca2+-dependent binding of titin's N2A region to thin filaments increases titin stiffness by preventing low-force straightening of proximal immunoglobulin domains that occurs during passive stretch. This mechanism explains the difference in length dependence of force between skeletal myofibrils and cardiac myocytes. Second, we hypothesize that cross-bridges serve not only as motors that pull thin filaments towards the M-line, but also as rotors that wind titin on the thin filaments, storing elastic potential energy in PEVK during force development and active stretch. Energy stored during force development can be recovered during active shortening. The winding filament hypothesis accounts for force enhancement during stretch and force depression during shortening, and provides testable predictions that will encourage new directions for research on mechanisms of muscle contraction.

Original languageEnglish (US)
Pages (from-to)981-990
Number of pages10
JournalProceedings of the Royal Society B: Biological Sciences
Issue number1730
StatePublished - 2012


  • Connectin
  • Force depression
  • Force enhancement
  • History dependence of force production
  • Thin filament rotation
  • Titin-actin interactions

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Immunology and Microbiology
  • General Environmental Science
  • General Agricultural and Biological Sciences


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