Imaging of Existing and Newly Translated Proteins Elucidates Mechanisms of Sarcomere Turnover.

Autor:	Douvdevany G; The Rappaport Family Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel (G.D., I.E., L.H.-C., T.M., I.K.)., Erlich I; The Rappaport Family Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel (G.D., I.E., L.H.-C., T.M., I.K.)., Haimovich-Caspi L; The Rappaport Family Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel (G.D., I.E., L.H.-C., T.M., I.K.)., Mashiah T; The Rappaport Family Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel (G.D., I.E., L.H.-C., T.M., I.K.)., Prondzynski M; Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany (M.P., L.C.).; German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Germany (M.P., L.C.).; Now with Department of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA (M.P.)., Pricolo MR; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.R.P., J.A.-C.)., Alegre-Cebollada J; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (M.R.P., J.A.-C.)., Linke WA; Institute of Physiology II, University of Munster, Germany (W.A.L.)., Carrier L; Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Germany (M.P., L.C.).; German Centre for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Germany (M.P., L.C.)., Kehat I; The Rappaport Family Institute and the Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel (G.D., I.E., L.H.-C., T.M., I.K.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 Aug 02; Vol. 135 (4), pp. 474-487. Date of Electronic Publication: 2024 Jul 04.
DOI:	10.1161/CIRCRESAHA.123.323819
Abstrakt:	Background: How the sarcomeric complex is continuously turned over in long-living cardiomyocytes is unclear. According to the prevailing model of sarcomere maintenance, sarcomeres are maintained by cytoplasmic soluble protein pools with free recycling between pools and sarcomeres. Methods: We imaged and quantified the turnover of expressed and endogenous sarcomeric proteins, including the giant protein titin, in cardiomyocytes in culture and in vivo, at the single cell and at the single sarcomere level using pulse-chase labeling of Halo-tagged proteins with covalent ligands. Results: We disprove the prevailing protein pool model and instead show an ordered mechanism in which only newly translated proteins enter the sarcomeric complex while older ones are removed and degraded. We also show that degradation is independent of protein age and that proteolytic extraction is a rate-limiting step in the turnover. We show that replacement of sarcomeric proteins occurs at a similar rate within cells and across the heart and is slower in adult cells. Conclusions: Our findings establish a unidirectional replacement model for cardiac sarcomeres subunit replacement and identify their turnover principles. Competing Interests: None.
Databáze:	MEDLINE
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