Titin: Physiological function and role in cardiomyopathy and failure

Henk L. Granzier, Yiming Wu, Labeit Siegfried, Martin LeWinter

Research output: Contribution to journalReview article

59 Scopus citations

Abstract

Titin is a giant protein that constitutes the third myofilament of the sarcomere. Single titin molecules anchor in the Z-disk and extend all the way to the M-line region of the sarcomere. Successive titin molecules are arranged head-to-head and tail-to-tail, providing a continuous filament along the full length of the myofibril. The majority of titin's I-band region is extensible and functions as a molecular spring that when extended develops passive force. We will discuss mechanisms for adjusting titin-based force, including alternative splicing and posttranslational modifications. Multiple biological functions can be assigned to different regions of the titin molecule. In addition to titin's role in determining passive muscle stiffness, recent evidence suggests a role in protein metabolism, compartmentalization of metabolic enzymes, binding of chaperones, and positioning of the membrane systems of the T-tubules and sarcoplasmic reticulum. We will also discus titin-based force adjustments that occur in various muscle diseases and several disease-causing titin mutations that have been discovered. We will focus on the role of titin in heart failure patients that was recently investigated in patients with end-stage heart failure due to non-ischemic dilated cardiomyopathy. In end-stage failing hearts, compliant titin isoforms comprise a greater percentage of titin and changes in titin isoform expression in heart failure patients with DCM significantly impact diastolic filling by lowering myocardial stiffness.

Original languageEnglish (US)
Pages (from-to)211-223
Number of pages13
JournalHeart Failure Reviews
Volume10
Issue number3
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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Keywords

  • Diastole
  • Passive stiffness
  • Stretch sensing
  • Titin isoforms

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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