Graded titin cleavage progressively reduces tension and uncovers the source of A-band stability in contracting muscle
Abstract
The giant muscle protein titin is a major contributor to passive force; however, its role in active force generation is unresolved. Here, we use a novel titin-cleavage (TC) mouse model that allows specific and rapid cutting of elastic titin to quantify how titin-based forces define myocyte ultrastructure and mechanics. We show that under mechanical strain, as titin cleavage doubles from heterozygous to homozygous TC muscles, Z-disks become increasingly out of register while passive and active forces are reduced. Interactions of elastic titin with sarcomeric actin filaments are revealed. Strikingly, when titin-cleaved muscles contract, myosin-containing A-bands become split and adjacent myosin filaments move in opposite directions while also shedding myosins. This establishes intact titin filaments as critical force-transmission networks, buffering the forces observed by myosin filaments during contraction. To perform this function, elastic titin must change stiffness or extensible length, unveiling its fundamental role as an activation-dependent spring in contracting muscle.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1 to 7.
Article and author information
Author details
Funding
German Research Foundation (SFB1002,TPA08)
- Wolfgang A Linke
IZKF Muenster (Li1/029/20)
- Wolfgang A Linke
European Research Area Network on Cardiovascular Disease consortium (MINOTAUR)
- Wolfgang A Linke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Alphee Michelot, Institut de Biologie du Développement, France
Ethics
Animal experimentation: Laboratory mice were bred and housed at the University Clinic Muenster, in strict accordance with, and approval from the local authorities (LANUV NRW, Germany, 81-02.04.2019.A472). All procedures were performed according to the guidelines of the animal care and use committee of the University Clinic Muenster. Adult mice were euthanized by an isoflurane gas overdose and cervical dislocation, as recommended by the local animal care and use committee, and every effort was made to minimize suffering.
Version history
- Received: October 17, 2020
- Accepted: December 23, 2020
- Accepted Manuscript published: December 24, 2020 (version 1)
- Version of Record published: January 4, 2021 (version 2)
Copyright
© 2020, Li et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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