Elastic titin properties and protein quality control in the aging heart

Senem Salcan, Sabine Bongardt, David Monteiro Barbosa, Igor R. Efimov, Tienush Rassaf, Martina Krüger*, Sebastian Kötter

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cardiac aging affects the heart on the functional, structural, and molecular level and shares characteristic hallmarks with the development of chronic heart failure. Apart from age-dependent left ventricular hypertrophy and fibrosis that impairs diastolic function, diminished activity of cardiac protein-quality-control systems increases the risk of cytotoxic accumulation of defective proteins. Here, we studied the impact of cardiac aging on the sarcomeric protein titin by analyzing titin-based cardiomyocyte passive tension, titin modification and proteasomal titin turnover. We analyzed left ventricular samples from young (6 months) and old (20 months) wild-type mice and healthy human donor patients grouped according to age in young (17–50 years) and aged hearts (51–73 years). We found no age-dependent differences in titin isoform composition of mouse or human hearts. In aged hearts from mice and human we determined altered titin phosphorylation at serine residues S4010 and S4099 in the elastic N2[sbnd]B domain, but no significant changes in phosphorylation of S11878 and S12022 in the elastic PEVK region. Importantly, overall titin-based cardiomyocyte passive tension remained unchanged. In aged hearts, the calcium-activated protease calpain-1, which provides accessibility to ubiquitination by releasing titin from the sarcomere, showed decreased proteolytic activity. In addition, we observed a reduction in the proteasomal activities. Taken together, our data indicate that cardiac aging does not affect titin-based passive properties of the cardiomyocytes, but impairs protein-quality control, including titin, which may result in a diminished adaptive capacity of the aged myocardium.

Original languageEnglish (US)
Article number118532
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1867
Issue number3
DOIs
StatePublished - Mar 2020
Externally publishedYes

Keywords

  • Connectin
  • Passive tension
  • Posttranslational modification
  • Proteasome

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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