Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy.

Autor:	Paulke NJ; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Fleischhacker C; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Wegener JB; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Riedemann GC; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Cretu C; Biochemistry of Membrane Dynamics Group, Institute for Auditory Neuroscience and InnerEarLab (C.C., J.P.), University Medical Center Göttingen, Germany., Mushtaq M; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Zaremba N; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Möbius W; Department of Neurogenetics, Electron Microscopy, City Campus (W.M.).; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Zühlke Y; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Wedemeyer J; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Liebmann L; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Gorshkova AA; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Kownatzki-Danger D; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Now with Institute of Transfusion Medicine, University Hospital Schleswig-Holstein; Kiel, Germany (D.K.-D)., Wagner E; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Kohl T; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany., Wichmann C; Molecular Architecture of Synapses Group, Institute for Auditory Neuroscience and InnerEarLab and Center for Biostructural Imaging of Neurodegeneration (C.W.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Jahn O; Translational Neuroproteomics Group, Department of Psychiatry and Psychotherapy (O.J.), University Medical Center Göttingen, Germany.; Neuroproteomics Group, Department of Molecular Neurobiology (O.J.)., Urlaub H; Department of Clinical Chemistry (H.U., C.L.), University Medical Center Göttingen, Germany.; Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany (H.U., C.L.).; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Toischer K; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.).; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Germany (K.T., G.H., S.E.L.)., Hasenfuß G; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.).; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Germany (K.T., G.H., S.E.L.)., Moser T; Institute for Auditory Neuroscience and InnerEarLab (T.M.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Preobraschenski J; Biochemistry of Membrane Dynamics Group, Institute for Auditory Neuroscience and InnerEarLab (C.C., J.P.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Lenz C; Department of Clinical Chemistry (H.U., C.L.), University Medical Center Göttingen, Germany.; Bioanalytical Mass Spectrometry Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany (H.U., C.L.).; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.)., Rog-Zielinska EA; Institute for Experimental Cardiovascular Medicine, University Heart Center and Faculty of Medicine, University of Freiburg, Germany (E.A.R.-Z.)., Lehnart SE; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.).; DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, Germany (K.T., G.H., S.E.L.)., Brandenburg S; Department of Cardiology and Pneumology (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., K.T., G.H., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cellular Biophysics and Translational Cardiology Section, Heart Research Center (N.J.P., C.F., J.B.W., G.C.R., M.M., N.Z., Y.Z., J.W., L.L., A.A.G., D.K.-D., E.W., T.K., S.E.L., S.B.), University Medical Center Göttingen, Germany.; Cluster of Excellence 'Multiscale Bioimaging: from Molecular Machines to Networks of Excitable Cells' (MBExC), University of Göttingen, Germany (W.M., C.W., H.U., K.T., G.H., T.M., J.P., C.L., S.E.L., S.B.).
Jazyk:	angličtina
Zdroj:	Circulation research [Circ Res] 2024 Aug 16; Vol. 135 (5), pp. 554-574. Date of Electronic Publication: 2024 Jul 16.
DOI:	10.1161/CIRCRESAHA.124.324588
Abstrakt:	Background: Cardiac hypertrophy compensates for increased biomechanical stress of the heart induced by prevalent cardiovascular pathologies but can result in heart failure if left untreated. Here, we hypothesized that the membrane fusion and repair protein dysferlin is critical for the integrity of the transverse-axial tubule (TAT) network inside cardiomyocytes and contributes to the proliferation of TAT endomembranes during pressure overload-induced cardiac hypertrophy. Methods: Stimulated emission depletion and electron microscopy were used to localize dysferlin in mouse and human cardiomyocytes. Data-independent acquisition mass spectrometry revealed the cardiac dysferlin interactome and proteomic changes of the heart in dysferlin-knockout mice. After transverse aortic constriction, we compared the hypertrophic response of wild-type versus dysferlin-knockout hearts and studied TAT network remodeling mechanisms inside cardiomyocytes by live-cell membrane imaging. Results: We localized dysferlin in a vesicular compartment in nanometric proximity to contact sites of the TAT network with the sarcoplasmic reticulum, a.k.a. junctional complexes for Ca 2+ -induced Ca 2+ release. Interactome analyses demonstrated a novel protein interaction of dysferlin with the membrane-tethering sarcoplasmic reticulum protein juncophilin-2, a putative interactor of L-type Ca 2+ channels and ryanodine receptor Ca 2+ release channels in junctional complexes. Although the dysferlin-knockout caused a mild progressive phenotype of dilated cardiomyopathy, global proteome analysis revealed changes preceding systolic failure. Following transverse aortic constriction, dysferlin protein expression was significantly increased in hypertrophied wild-type myocardium, while dysferlin-knockout animals presented markedly reduced left-ventricular hypertrophy. Live-cell membrane imaging showed a profound reorganization of the TAT network in wild-type left-ventricular myocytes after transverse aortic constriction with robust proliferation of axial tubules, which critically depended on the increased expression of dysferlin within newly emerging tubule components. Conclusions: Dysferlin represents a new molecular target in cardiac disease that protects the integrity of tubule-sarcoplasmic reticulum junctional complexes for regulated excitation-contraction coupling and controls TAT network reorganization and tubular membrane proliferation in cardiomyocyte hypertrophy induced by pressure overload. Competing Interests: None.
Databáze:	MEDLINE
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