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Titin: Physiological Function and Role in Cardiomyopathy and Failure

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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.

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Authors and Affiliations

  1. Dept. of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, USA

    Henk Granzier PhD & Yiming Wu MD, PhD

  2. Institut für Anästhesiologie und Operative Intensivmedizin, Universitätsklinikum Mannheim, Mannheim, 68167, Germany

    Labeit Siegfried

  3. Fletcher Allen Health Care, 111 Colchester Ave, Burlington, 05401, VT, USA

    Martin LeWinter MD

  4. Washington State University, Wegner Hall 205, Pullman, 99164-6520, wa, USA

    Henk Granzier PhD

Authors
  1. Henk Granzier PhD
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  2. Yiming Wu MD, PhD
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  3. Labeit Siegfried
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  4. Martin LeWinter MD
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Corresponding author

Correspondence to Henk Granzier PhD.

Additional information

This study was supported by grants from the National Institutes of Health, HL61487 and HL62881.

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Granzier, H., Wu, Y., Siegfried, L. et al. Titin: Physiological Function and Role in Cardiomyopathy and Failure. Heart Fail Rev 10, 211–223 (2005). https://doi.org/10.1007/s10741-005-5251-7

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