Canzhao Liu1, Simone Spinozzi1, Jia-Yu Chen2, Xi Fang1, Wei Feng1, Guy Perkins3, Paola Cattaneo4,5, Nuno Guimarães-Camboa6,7, Nancy D Dalton1, Kirk L Peterson1, Tongbin Wu1, Kunfu Ouyang8, Xiang-Dong Fu2,9, Sylvia M Evans1,10, Ju Chen1. 1. Department of Medicine (C.L., S.S., X.F., W.F., N.D.D., K.L.P., T.W., S.M.E., J.C.), University of California, San Diego, La Jolla. 2. Department of Cellular and Molecular Medicine (J.-Y.C., X.-D.F.), University of California, San Diego, La Jolla. 3. National Center for Microscopy and Imaging Research (G.P.), University of California, San Diego, La Jolla. 4. National Research Council, Institute of Genetics and Biomedical Research, Milan, Italy (P.C.). 5. Humanitas Clinical and Research Center, Rozzano, Italy (P.C.). 6. Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, Goethe University Frankfurt, Germany (N.G.-C.). 7. German Center for Cardiovascular Research DZHK, Berlin (N.G.-C.). 8. Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, China (K.O.). 9. Institute of Genomic Medicine (X.D.-F.), University of California, San Diego, La Jolla. 10. Department of Pharmacology, Skaggs School of Pharmacy and Pharmaceutical Sciences (S.M.E.), University of California, San Diego, La Jolla.
Abstract
BACKGROUND: Membrane contact sites are fundamental for transmission and translation of signals in multicellular organisms. The junctional membrane complexes in the cardiac dyads, where transverse (T) tubules are juxtaposed to the sarcoplasmic reticulum, are a prime example. T-tubule uncoupling and remodeling are well-known features of cardiac disease and heart failure. Even subtle alterations in the association between T-tubules and the junctional sarcoplasmic reticulum can cause serious cardiac disorders. NEXN (nexilin) has been identified as an actin-binding protein, and multiple mutations in the NEXN gene are associated with cardiac diseases, but the precise role of NEXN in heart function and disease is still unknown. METHODS: Nexn global and cardiomyocyte-specific knockout mice were generated. Comprehensive phenotypic and RNA sequencing and mass spectrometry analyses were performed. Heart tissue samples and isolated single cardiomyocytes were analyzed by electron and confocal microscopy. RESULTS: Global and cardiomyocyte-specific loss of Nexn in mice resulted in a rapidly progressive dilated cardiomyopathy. In vivo and in vitro analyses revealed that NEXN interacted with junctional sarcoplasmic reticulum proteins, was essential for optimal calcium transients, and was required for initiation of T-tubule invagination and formation. CONCLUSIONS: These results demonstrated that NEXN is a pivotal component of the junctional membrane complex and is required for initiation and formation of T-tubules, thus providing insight into mechanisms underlying cardiomyopathy in patients with mutations in NEXN.
BACKGROUND: Membrane contact sites are fundamental for transmission and translation of signals in multicellular organisms. The junctional membrane complexes in the cardiac dyads, where transverse (T) tubules are juxtaposed to the sarcoplasmic reticulum, are a prime example. T-tubule uncoupling and remodeling are well-known features of cardiac disease and heart failure. Even subtle alterations in the association between T-tubules and the junctional sarcoplasmic reticulum can cause serious cardiac disorders. NEXN (nexilin) has been identified as an actin-binding protein, and multiple mutations in the NEXN gene are associated with cardiac diseases, but the precise role of NEXN in heart function and disease is still unknown. METHODS:Nexn global and cardiomyocyte-specific knockout mice were generated. Comprehensive phenotypic and RNA sequencing and mass spectrometry analyses were performed. Heart tissue samples and isolated single cardiomyocytes were analyzed by electron and confocal microscopy. RESULTS: Global and cardiomyocyte-specific loss of Nexn in mice resulted in a rapidly progressive dilated cardiomyopathy. In vivo and in vitro analyses revealed that NEXN interacted with junctional sarcoplasmic reticulum proteins, was essential for optimal calcium transients, and was required for initiation of T-tubule invagination and formation. CONCLUSIONS: These results demonstrated that NEXN is a pivotal component of the junctional membrane complex and is required for initiation and formation of T-tubules, thus providing insight into mechanisms underlying cardiomyopathy in patients with mutations in NEXN.
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