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 N2B 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.
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