Cardiac titin: Structure, functions and role in disease

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

Research output: Contribution to journalReview article

83 Scopus citations

Abstract

Titin is a giant sarcomeric protein found in both cardiac and skeletal muscle. In the heart, the structure, functions and role of titin in disease have begun to be elucidated over the last decade. Titin's N-terminus is anchored in the Z-disk while C-terminal domains are bound to the thick filament. The I-band segment is a complex molecular spring consisting of PEVK and tandem Ig segments as well as variable N2B and N2A elements. The latter determine titin's two isoforms. N2B alone is present in the smaller and stiffer N2B isoform and both N2A and N2B elements are present in the larger, more compliant N2BA isoform. Large mammals co-express both isoforms, while normal rodents have virtually exclusively N2B titin. With sarcomere stretch, titin's I-band segment elongates and develops passive tension. Titin is the predominant determinant of cardiomyocyte passive tension over the physiologic sarcomere length range. With contraction below slack length, the thick filament drags titin in the opposite direction such that extension of the spring results in generation of a restoring force resulting in elastic recoil. In addition to its mechanical properties, a role is emerging for titin as a major biomechanical sensing and signaling molecule. Moreover, recent studies indicate that titin undergoes dynamic isoform and possibly phosphorylation changes in disease.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalClinica Chimica Acta
Volume375
Issue number1-2
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Keywords

  • Diastolic ventricular function
  • Passive myocardial stiffness
  • Restoring forces
  • Titin

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Biochemistry, medical

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