Maintenance of sarcomeric integrity in adult muscle cells crucially depends on Z-disc anchored titin
2020 | journal article; research paper
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Maintenance of sarcomeric integrity in adult muscle cells crucially depends on Z-disc anchored titin
Swist, S.; Unger, A.; Li, Y.; Vöge, A.; von Frieling-Salewsky, M.; Skärlén, Å. & Cacciani, N. et al. (2020)
Nature Communications, 11(1) pp. 4479. DOI: https://doi.org/10.1038/s41467-020-18131-2
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Details
- Authors
- Swist, Sandra; Unger, Andreas; Li, Yong; Vöge, Anja; von Frieling-Salewsky, Marion; Skärlén, Åsa; Cacciani, Nicola; Braun, Thomas; Larsson, Lars; Linke, Wolfgang A.
- 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.
- Issue Date
- 2020
- Journal
- Nature Communications
- Project
- SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz
SFB 1002 | A08: Translationale und posttranslationale Kontrolle trunkierter Titinproteine in Kardiomyozyten von Patienten mit dilatativer Kardiomyopathie - Working Group
- RG Linke (Kardiovaskuläre Physiologie)
- ISSN
- 2041-1723
- Language
- English