P514Telethonin, Z-disc and myocardial performance

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Abstract

Purpose

Telethonin (also known as titin-cap or t-cap, TCAP) is a 19 kDa Z-disc protein which assembles in a palindromic way with the N-terminal portion of titin and participates in the process of cardiac mechanosensing.

Purpose

However, a variety of telethonin mutations are associated with the development of several different diseases, but little is known about the underlying molecular mechanisms and telethonin's in vivo function, which we attempt to unravel.

Methods & Results

We generated telethonin knockout (ko), telethonin transgenic overexpressing and telethonin ko/dominant negative p53 (dnp53) double transgenic animals and performed a variety of biophysical experiments. Contrary to previous views, telethonin is not an indispensable component of the titin-anchoring system, nor is cardiac specific overexpression of this gene associated with a spontaneous cardiac phenotype. However, telethonin ko animals developed maladaptive cardiac hypertrophy and severe heart failure upon biomechanical stress induced via transverse aortic constriction (TAC) or via anthracycline treatment. We also found a significant increase in apoptotic cardiac myocytes as judged by TUNEL analysis. This was accompanied by a significant increase in p53 protein levels and co-localization of telethonin with p53 in the nuclear compartment. Moreover, co-immunoprecipation, pull down and overlay assays together with static light scattering, Surface Plasmon Resonance (SPR) and NMR analysis confirmed that telethonin interacts with the p53 DNA-binding domain (p53DBD).

Methods & Results

Interestingly, overexpression of telethonin was associated with decreased p53 protein levels in vitro as well as in vivo, which suggests that a novel function of telethonin might be to modulate the turnover of the proapoptotic tumor suppressor p53 in the nuclear compartment after biomechanical stress.

Methods & Results

Noteworthily, telethonin ko/dnp53 double transgenic animals are protected against apoptosis following TAC and loss of telethonin mRNA and nuclear accumulation of this protein is associated with human heart failure.

Conclusion

Telethonin deficient animals do not develop a spontaneous phenotype but develop heart failure due to apoptosis upon biomechanical stress either by pressure overload or oxidative stress, an effect which might be called "mechanoptosis". Furthermore, telethonin modulates this effect i) via the turnover of the proapoptotic tumor suppressor p53 in the nuclear compartment and ii) probably via its direct interference with the DNA binding domain of this transcription factor ("Z-disk mechanotranscriptional coupling, ZMTC").

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