ArticleCirculation research2011
Telethonin deficiency is associated with maladaptation to biomechanical stress in the mammalian heart.
Article in Circulation research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 98 citations in OpenAlex.
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- How Localized Z-Disc Damage Affects Force Generation and Gene Expression in Cardiomyocytes.Bioengineering (Basel, Switzerland) · 2021Article
- Striated muscle proteins are regulated both by mechanical deformation and by chemical post-translational modification.Biophysical reviews · 2021Review
- Multi-omics approaches for revealing the complexity of cardiovascular disease.Briefings in bioinformatics · 2021Review
- Novel insights into sarcomere regulatory systems control of cardiac thin filament activation.The Journal of general physiology · 2021Article
- Mechanosignaling pathways alter muscle structure and function by post-translational modification of existing sarcomeric proteins to optimize energy usage.Journal of muscle research and cell motility · 2021Article
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Authors and funding
34 authors at 3 institutions in 2 countries.
Funding
Abstract
rationaleTelethonin (also known as titin-cap or t-cap) is a 19-kDa Z-disk protein with a unique β-sheet structure, hypothesized to assemble in a palindromic way with the N-terminal portion of titin and to constitute a signalosome participating in the process of cardiomechanosensing. In addition, a variety of telethonin mutations are associated with the development of several different diseases; however, little is known about the underlying molecular mechanisms and telethonin's in vivo function.
objectiveHere we aim to investigate the role of telethonin in vivo and to identify molecular mechanisms underlying disease as a result of its mutation. METHODS AND
resultsBy using a variety of different genetically altered animal models and biophysical experiments we show that contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is deletion of the gene or cardiac specific overexpression associated with a spontaneous cardiac phenotype. Rather, additional titin-anchorage sites, such as actin-titin cross-links via α-actinin, are sufficient to maintain Z-disk stability despite the loss of telethonin. We demonstrate that a main novel function of telethonin is to modulate the turnover of the proapoptotic tumor suppressor p53 after biomechanical stress in the nuclear compartment, thus linking telethonin, a protein well known to be present at the Z-disk, directly to apoptosis ("mechanoptosis"). In addition, loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure, an effect that may contribute to enhanced rates of apoptosis found in these hearts.
conclusionsTelethonin knockout mice do not reveal defective heart development or heart function under basal conditions, but develop heart failure following biomechanical stress, owing at least in part to apoptosis of cardiomyocytes, an effect that may also play a role in human heart failure.
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