Maintenance of sarcomeric integrity in adult muscle cells crucially depends on Z-disc anchored titin

Sandra Swist (), Andreas Unger, Yong Li, Anja Vöge, Marion Frieling-Salewsky, Åsa Skärlén, Nicola Cacciani, Thomas Braun, Lars Larsson and Wolfgang A. Linke ()
Additional contact information
Sandra Swist: Ruhr University Bochum
Andreas Unger: University of Munster
Yong Li: University of Munster
Anja Vöge: Ruhr University Bochum
Marion Frieling-Salewsky: University of Munster
Åsa Skärlén: Clinical Neurophysiology, Karolinska Institute
Nicola Cacciani: Karolinska Institute
Thomas Braun: Max Planck Institute for Heart and Lung Research
Lars Larsson: Karolinska Institute
Wolfgang A. Linke: University of Munster

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: Abstract The giant protein titin is thought to be required for sarcomeric integrity in mature myocytes, but direct evidence for this hypothesis is limited. Here, we describe a mouse model in which Z-disc-anchored TTN is depleted in adult skeletal muscles. Inactivation of TTN causes sarcomere disassembly and Z-disc deformations, force impairment, myocyte de-stiffening, upregulation of TTN-binding mechanosensitive proteins and activation of protein quality-control pathways, concomitant with preferential loss of thick-filament proteins. Interestingly, expression of the myosin-bound Cronos-isoform of TTN, generated from an alternative promoter not affected by the targeting strategy, does not prevent deterioration of sarcomere formation and maintenance. Finally, we demonstrate that loss of Z-disc-anchored TTN recapitulates muscle remodeling in critical illness ‘myosinopathy’ patients, characterized by TTN-depletion and loss of thick filaments. We conclude that full-length TTN is required to integrate Z-disc and A-band proteins into the mature sarcomere, a function that is lost when TTN expression is pathologically lowered.

Date: 2020
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-020-18131-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18131-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-020-18131-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().