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  Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction.

Wagner, E., Lauterbach, M., Kohl, T., Westphal, V., Williams, S. B., Steinbrecher, J. H., et al. (2012). Stimulated emission depletion live-cell super-resolution imaging shows proliferative remodeling of T-tubule membrane structures after myocardial infarction. Circulation Research, 111(4), 402-414. doi:10.1161/CIRCRESAHA.112.274530.

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Wagner, E., Autor
Lauterbach, M.1, Autor           
Kohl, T., Autor
Westphal, V.1, Autor           
Williams, S. B., Autor
Steinbrecher, J. H., Autor
Streich, J., Autor
Korff, B., Autor
Tuan, M., Autor
Hagen, B., Autor
Luther, S., Autor
Hasenfuss, G., Autor
Parlitz, U., Autor
Saleet Jafri, M., Autor
Hell, S. W.1, Autor                 
Lederer, W. J., Autor
Lehnart, S. E., Autor
Affiliations:
1Department of NanoBiophotonics, MPI for biophysical chemistry, Max Planck Society, ou_578627              

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Schlagwörter: Ca2+ sparks; excitation-contraction coupling; heart failure; T-tubule; super-resolution imaging; calcium signaling
 Zusammenfassung: Rationale: Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca2+ release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). Objectives: Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. Methods and Results: Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT-associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca2+ release and action potential prolongation. Conclusions: This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca2+ release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing.

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Sprache(n): eng - English
 Datum: 2012-06-212012-08-03
 Publikationsstatus: Erschienen
 Seiten: -
 Ort, Verlag, Ausgabe: -
 Inhaltsverzeichnis: -
 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1161/CIRCRESAHA.112.274530
 Art des Abschluß: -

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Titel: Circulation Research
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: -
Seiten: - Band / Heft: 111 (4) Artikelnummer: - Start- / Endseite: 402 - 414 Identifikator: -