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Dysferlin Enables Tubular Membrane Proliferation in Cardiac Hypertrophy.
Paulke, Nora Josefine; Fleischhacker, Carolin; Wegener, Justus B; Riedemann, Gabriel C; Cretu, Constantin; Mushtaq, Mufassra; Zaremba, Nina; Möbius, Wiebke; Zühlke, Yannik; Wedemeyer, Jasper; Liebmann, Lorenz; Gorshkova, Anastasiia A; Kownatzki-Danger, Daniel; Wagner, Eva; Kohl, Tobias; Wichmann, Carolin; Jahn, Olaf; Urlaub, Henning; Toischer, Karl; Hasenfuß, Gerd; Moser, Tobias; Preobraschenski, Julia; Lenz, Christof; Rog-Zielinska, Eva A; Lehnart, Stephan E; Brandenburg, Sören.
Afiliação
  • 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.
  • Fleischhacker C; 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.
  • Riedemann GC; 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; 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.
  • Mushtaq M; 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.
  • Möbius W; 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.
  • Zühlke Y; Biochemistry of Membrane Dynamics Group, Institute for Auditory Neuroscience and InnerEarLab (C.C., J.P.), 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.
  • Liebmann L; 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.
  • Kownatzki-Danger D; 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.
  • Wagner E; Department of Neurogenetics, Electron Microscopy, City Campus (W.M.).
  • Kohl T; 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.).
  • Wichmann 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.
  • Jahn O; 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.
  • Urlaub H; 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.
  • Toischer K; 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.
  • 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.
  • Moser T; 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.
  • Preobraschenski 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.
  • Lenz C; 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.
  • Rog-Zielinska EA; 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.
  • Lehnart SE; 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.
  • Brandenburg S; Now with Institute of Transfusion Medicine, University Hospital Schleswig-Holstein; Kiel, Germany (D.K.-D).
Circ Res ; 135(5): 554-574, 2024 Aug 16.
Article em En | MEDLINE | ID: mdl-39011635
ABSTRACT

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 Ca2+-induced Ca2+ 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 Ca2+ channels and ryanodine receptor Ca2+ 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Retículo Sarcoplasmático / Cardiomegalia / Camundongos Knockout / Miócitos Cardíacos / Disferlina Limite: Animals / Humans / Male Idioma: En Revista: Circ Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Retículo Sarcoplasmático / Cardiomegalia / Camundongos Knockout / Miócitos Cardíacos / Disferlina Limite: Animals / Humans / Male Idioma: En Revista: Circ Res Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Alemanha