Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy

Ambjorn Brynnel, Yaeren Hernandez, Balazs Kiss, Johan Lindqvist, Maya Adler, Justin Kolb, Robbert van der Pijl, Jochen Gohlke, Joshua Strom, John Smith, Coen Ottenheijm, Henk L Granzier

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin's contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin's molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.

Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Original languageEnglish
Article numbere40532
JournaleLife
Volume7
DOIs
Publication statusPublished - 19 Dec 2018

Cite this

Brynnel, Ambjorn ; Hernandez, Yaeren ; Kiss, Balazs ; Lindqvist, Johan ; Adler, Maya ; Kolb, Justin ; van der Pijl, Robbert ; Gohlke, Jochen ; Strom, Joshua ; Smith, John ; Ottenheijm, Coen ; Granzier, Henk L. / Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy. In: eLife. 2018 ; Vol. 7.
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title = "Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy",
abstract = "Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin's contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin's molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30{\%} increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).",
author = "Ambjorn Brynnel and Yaeren Hernandez and Balazs Kiss and Johan Lindqvist and Maya Adler and Justin Kolb and {van der Pijl}, Robbert and Jochen Gohlke and Joshua Strom and John Smith and Coen Ottenheijm and Granzier, {Henk L}",
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Downsizing the molecular spring of the giant protein titin reveals that skeletal muscle titin determines passive stiffness and drives longitudinal hypertrophy. / Brynnel, Ambjorn; Hernandez, Yaeren; Kiss, Balazs; Lindqvist, Johan; Adler, Maya; Kolb, Justin; van der Pijl, Robbert; Gohlke, Jochen; Strom, Joshua; Smith, John; Ottenheijm, Coen; Granzier, Henk L.

In: eLife, Vol. 7, e40532, 19.12.2018.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Brynnel, Ambjorn

AU - Hernandez, Yaeren

AU - Kiss, Balazs

AU - Lindqvist, Johan

AU - Adler, Maya

AU - Kolb, Justin

AU - van der Pijl, Robbert

AU - Gohlke, Jochen

AU - Strom, Joshua

AU - Smith, John

AU - Ottenheijm, Coen

AU - Granzier, Henk L

N1 - © 2018, Brynnel et al.

PY - 2018/12/19

Y1 - 2018/12/19

N2 - Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin's contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin's molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

AB - Titin, the largest protein known, forms an elastic myofilament in the striated muscle sarcomere. To establish titin's contribution to skeletal muscle passive stiffness, relative to that of the extracellular matrix, a mouse model was created in which titin's molecular spring region was shortened by deleting 47 exons, the TtnΔ112-158 model. RNA sequencing and super-resolution microscopy predicts a much stiffer titin molecule. Mechanical studies with this novel mouse model support that titin is the main determinant of skeletal muscle passive stiffness. Unexpectedly, the in vivo sarcomere length working range was shifted to shorter lengths in TtnΔ112-158 mice, due to a ~ 30% increase in the number of sarcomeres in series (longitudinal hypertrophy). The expected effect of this shift on active force generation was minimized through a shortening of thin filaments that was discovered in TtnΔ112-158 mice. Thus, skeletal muscle titin is the dominant determinant of physiological passive stiffness and drives longitudinal hypertrophy.Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

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