Deleting titin's I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function

Hendrikus "Henk" Granzier, Kirk R. Hutchinson, Paola Tonino, Mei Methawasin, Frank W. Li, Rebecca E. Slater, Mathew M. Bull, Chandra Saripalli, Christopher T. Pappas, Carol Gregorio, John E. Smith

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Titin, the largest protein known, forms a giant filament in muscle where it spans the half sarcomere from Z disk to M band. Here we genetically targeted a stretch of 14 immunoglobulin-like and fibronectin type 3 domains that comprises the I-band/A-band (IA) junction and obtained a viable mouse model. Super-resolution optical microscopy (structured illumination microscopy, SIM) and electron microscopy were used to study the thick filament length and titin's molecular elasticity. SIM showed that the IA junction functionally belongs to the relatively stiff A-band region of titin. The stiffness of A-band titin was found to be high, relative to that of I-band titin (∼ 40-fold higher) but low, relative to that of the myosin-based thick filament (∼ 70-fold lower). Sarcomere stretch therefore results in movement of A-band titin with respect to the thick filament backbone, and this might constitute a novel length-sensing mechanism. Findings disproved that titin at the IA junction is crucial for thick filament length control, settling a long-standing hypothesis. SIM also showed that deleting the IA junction moves the attachment point of titin's spring region away from the Z disk, increasing the strain on titin's molecular spring elements. Functional studies from the cellular to ex vivo and in vivo left ventricular chamber levels showed that this causes diastolic dysfunction and other symptoms of heart failure with preserved ejection fraction (HFpEF). Thus, our work supports titin's important roles in diastolic function and disease of the heart.

Original languageEnglish (US)
Pages (from-to)14589-14594
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number40
DOIs
StatePublished - Oct 7 2014

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Connectin
Microscopy
Lighting
Sarcomeres
Elasticity
Myosins
Immunoglobulins
Heart Diseases
Electron Microscopy
Heart Failure

Keywords

  • hypertrophy
  • mechanosensing
  • molecular elasticity
  • passive stiffness

ASJC Scopus subject areas

  • General

Cite this

Deleting titin's I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function. / Granzier, Hendrikus "Henk"; Hutchinson, Kirk R.; Tonino, Paola; Methawasin, Mei; Li, Frank W.; Slater, Rebecca E.; Bull, Mathew M.; Saripalli, Chandra; Pappas, Christopher T.; Gregorio, Carol; Smith, John E.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 40, 07.10.2014, p. 14589-14594.

Research output: Contribution to journalArticle

Granzier, Hendrikus "Henk" ; Hutchinson, Kirk R. ; Tonino, Paola ; Methawasin, Mei ; Li, Frank W. ; Slater, Rebecca E. ; Bull, Mathew M. ; Saripalli, Chandra ; Pappas, Christopher T. ; Gregorio, Carol ; Smith, John E. / Deleting titin's I-band/A-band junction reveals critical roles for titin in biomechanical sensing and cardiac function. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 40. pp. 14589-14594.
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AU - Tonino, Paola

AU - Methawasin, Mei

AU - Li, Frank W.

AU - Slater, Rebecca E.

AU - Bull, Mathew M.

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