TY - JOUR
T1 - Elastic titin properties and protein quality control in the aging heart
AU - Salcan, Senem
AU - Bongardt, Sabine
AU - Monteiro Barbosa, David
AU - Efimov, Igor R.
AU - Rassaf, Tienush
AU - Krüger, Martina
AU - Kötter, Sebastian
N1 - Funding Information:
This work was supported by a grant from the Else Kröner-Fresenius-Stiftung , Germany ( 2017_A01 to S.K.), a grant from the Research Commission of the Medical Faculty, Heinrich-Heine-University , Germany ( 11/2014 to S.K.) and by the Deutsche Forschungsgemeinschaft ( SFB1116-1 TPA02 to M.K.)
Publisher Copyright:
© 2019 Elsevier B.V.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - Connectin
KW - Passive tension
KW - Posttranslational modification
KW - Proteasome
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U2 - 10.1016/j.bbamcr.2019.118532
DO - 10.1016/j.bbamcr.2019.118532
M3 - Article
C2 - 31421188
AN - SCOPUS:85072092680
SN - 0167-4889
VL - 1867
JO - Biochimica et Biophysica Acta - Molecular Cell Research
JF - Biochimica et Biophysica Acta - Molecular Cell Research
IS - 3
M1 - 118532
ER -
