{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:15:33Z","timestamp":1791224133705,"version":"4.1.0"},"reference-count":61,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"17","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2024,4,23]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Cardiac transverse tubules (T-tubules) are anchored to sarcomeric Z-discs by costameres to establish a regular spaced pattern. One of the major components of costameres is the dystrophin-glycoprotein complex (DGC). Nevertheless, how the assembly of the DGC coordinates with the formation and maintenance of T-tubules under physiological and pathological conditions remains unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              Given the known role of Ptpn23 (protein tyrosine phosphatase, nonreceptor type 23) in regulating membrane deformation, its expression in patients with dilated cardiomyopathy was determined. Taking advantage of Cre\/Loxp, CRISPR\/Cas9, and adeno-associated virus 9 (AAV9)\u2013mediated in vivo gene editing, we generated cardiomyocyte-specific\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              and\n              <jats:italic toggle=\"yes\">Actn2<\/jats:italic>\n              (\u03b1-actinin-2, a major component of Z-discs) knockout mice. We also perturbed the DGC by using dystrophin global knockout mice (\n              <jats:italic toggle=\"yes\">Dmd<\/jats:italic>\n              <jats:sup>E4*<\/jats:sup>\n              ). MM 4-64 and Di-8-ANEPPS staining, Cav3 immunofluorescence, and transmission electron microscopy were performed to determine T-tubule structure in isolated cells and intact hearts. In addition, the assembly of the DGC with\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              and dystrophin loss of function was determined by glycerol-gradient fractionation and SDS-PAGE analysis.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              The expression level of Ptpn23 was reduced in failing hearts from dilated cardiomyopathy patients and mice. Genetic deletion of\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              resulted in disorganized T-tubules with enlarged diameters and progressive dilated cardiomyopathy without affecting sarcomere organization. AAV9-mediated mosaic somatic mutagenesis further indicated a cell-autonomous role of\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              in regulating T-tubule formation. Genetic and biochemical analyses showed that Ptpn23 was essential for the integrity of costameres, which anchor the T-tubule membrane to Z-discs, through interactions with \u03b1-actinin and dystrophin. Deletion of \u03b1-actinin altered the subcellular localization of Ptpn23 and DGCs. In addition, genetic inactivation of dystrophin caused similar T-tubule defects to\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              loss-of-function without affecting Ptpn23 localization at Z-discs. Last, inducible\n              <jats:italic toggle=\"yes\">Ptpn23<\/jats:italic>\n              knockout at 1 month of age showed Ptpn23 is also required for the maintenance of T-tubules in adult cardiomyocytes.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Ptpn23 is essential for cardiac T-tubule formation and maintenance along Z-discs. During postnatal heart development, Ptpn23 interacts with sarcomeric \u03b1-actinin and coordinates the assembly of the DGC at costameres to sculpt T-tubule spatial patterning and morphology.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.123.065767","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T05:00:48Z","timestamp":1705035648000},"page":"1375-1390","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex"],"prefix":"10.1161","volume":"149","author":[{"given":"Chen","family":"Xu","sequence":"first","affiliation":[{"name":"Center for Genetic Medicine, The Fourth Affiliated Hospital (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.), Zhejiang University School of Medicine, Hangzhou, China."},{"name":"Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)."},{"name":"Zhejiang Provincial Key Laboratory of Genetic &amp; Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Genetic Medicine, The Fourth Affiliated Hospital (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.), Zhejiang University School of Medicine, Hangzhou, China."},{"name":"Institute of Genetics, Zhejiang University International School of Medicine, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)."},{"name":"Zhejiang Provincial Key Laboratory of Genetic &amp; Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., 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