Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex

Chen Xu; Ge Zhang; Xinjian Wang; Xiaozhi Huang; Jiayin Zhang; Shuxian Han; Jinxi Wang; Duane D Hall; Ruoqing Xu; Feng He; Xing Chang; Fudi Wang; Wenjun Xie; Zhichao Wu; Long-Sheng Song; Peidong Han

doi:10.1161/CIRCULATIONAHA.123.065767

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Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex

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Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex

Chen Xu, Ge Zhang, Xinjian Wang, Xiaozhi Huang, Jiayin Zhang, Shuxian Han, Jinxi Wang, Duane D Hall, Ruoqing Xu, Feng He, …

Circulation (New York, N.Y.), Vol.149(17), pp.1375-1390

04/23/2024

DOI: 10.1161/CIRCULATIONAHA.123.065767

PMCID: PMC11039371

PMID: 38214189

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Abstract

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. 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)-mediated in vivo gene editing, we generated cardiomyocyte-specific and (α-actinin-2, a major component of Z-discs) knockout mice. We also perturbed the DGC by using dystrophin global knockout mice ( ). 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 and dystrophin loss of function was determined by glycerol-gradient fractionation and SDS-PAGE analysis. The expression level of Ptpn23 was reduced in failing hearts from dilated cardiomyopathy patients and mice. Genetic deletion of 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 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 α-actinin and dystrophin. Deletion of α-actinin altered the subcellular localization of Ptpn23 and DGCs. In addition, genetic inactivation of dystrophin caused similar T-tubule defects to loss-of-function without affecting Ptpn23 localization at Z-discs. Last, inducible knockout at 1 month of age showed Ptpn23 is also required for the maintenance of T-tubules in adult cardiomyocytes. Ptpn23 is essential for cardiac T-tubule formation and maintenance along Z-discs. During postnatal heart development, Ptpn23 interacts with sarcomeric α-actinin and coordinates the assembly of the DGC at costameres to sculpt T-tubule spatial patterning and morphology.

dystrophin-glycoprotein complex

costameres

Ptpn23

T-tubule

Details

Title: Subtitle: Ptpn23 Controls Cardiac T-Tubule Patterning by Promoting the Assembly of Dystrophin-Glycoprotein Complex
Creators: Chen Xu - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Ge Zhang - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Xinjian Wang - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Xiaozhi Huang - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Jiayin Zhang - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Shuxian Han - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Jinxi Wang - University of Iowa
Duane D Hall - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City (J.W., D.D.H., L.-S.S.)
Ruoqing Xu - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Feng He - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Xing Chang - Westlake University
Fudi Wang - Zhejiang University
Wenjun Xie - First Affiliated Hospital of Xi'an Jiaotong University
Zhichao Wu - Sun Yat-sen University
Long-Sheng Song - Department of Internal Medicine, Abboud Cardiovascular Research Center, Carver College of Medicine, University of Iowa, Iowa City (J.W., D.D.H., L.-S.S.)
Peidong Han - Zhejiang Provincial Key Laboratory of Genetic & Developmental Disorders, Hangzhou, China (C.X., G.Z., X.W., X.H., J.Z., S.H., R.X., F.H., P.H.)
Resource Type: Journal article
Publication Details: Circulation (New York, N.Y.), Vol.149(17), pp.1375-1390
DOI: 10.1161/CIRCULATIONAHA.123.065767
PMID: 38214189
PMCID: PMC11039371
NLM abbreviation: Circulation
eISSN: 1524-4539
Language: English
Electronic publication date: 01/12/2024
Date published: 04/23/2024
Academic Unit: Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984543459502771

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