Tmem65 is critical for the structure and function of the intercalated discs in mouse hearts

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dc.contributor.authorTeng, Allen C. T.en
dc.contributor.authorGu, Liyangen
dc.contributor.authorDi Paola, Michelleen
dc.contributor.authorLakin, Roberten
dc.contributor.authorWilliams, Zachary J.en
dc.contributor.authorAu, Aaronen
dc.contributor.authorChen, Wenliangen
dc.contributor.authorCallaghan, Nealen
dc.contributor.authorZadeh, Farigol Hakemen
dc.contributor.authorZhou, Yu-Qingen
dc.contributor.authorFatah, Meenaen
dc.contributor.authorChatterjee, Diptenduen
dc.contributor.authorJourdan, L. Janeen
dc.contributor.authorLiu, Jacken
dc.contributor.authorSimmons, Craig A.en
dc.contributor.authorKislinger, Thomasen
dc.contributor.authorYip, Christopher M.en
dc.contributor.authorBackx, Peter H.en
dc.contributor.authorGourdie, Robert G.en
dc.contributor.authorHamilton, Robert M.en
dc.contributor.authorGramolini, Anthony O.en
dc.date.accessioned2024-09-30T13:45:39Zen
dc.date.available2024-09-30T13:45:39Zen
dc.date.issued2022-10-18en
dc.description.abstractThe intercalated disc (ICD) is a unique membrane structure that is indispensable to normal heart function, yet its structural organization is not completely understood. Previously, we showed that the ICD-bound transmembrane protein 65 (Tmem65) was required for connexin43 (Cx43) localization and function in cultured mouse neonatal cardiomyocytes. Here, we investigate the functional and cellular effects of Tmem65 reductions on the myocardium in a mouse model by injecting CD1 mouse pups (3–7 days after birth) with recombinant adeno-associated virus 9 (rAAV9) harboring Tmem65 shRNA, which reduces Tmem65 expression by 90% in mouse ventricles compared to scrambled shRNA injection. Tmem65 knockdown (KD) results in increased mortality which is accompanied by eccentric hypertrophic cardiomyopathy within 3 weeks of injection and progression to dilated cardiomyopathy with severe cardiac fibrosis by 7 weeks post-injection. Tmem65 KD hearts display depressed hemodynamics as measured echocardiographically as well as slowed conduction in optical recording accompanied by prolonged PR intervals and QRS duration in electrocardiograms. Immunoprecipitation and super-resolution microscopy demonstrate a physical interaction between Tmem65 and sodium channel β subunit (β1) in mouse hearts and this interaction appears to be required for both the establishment of perinexal nanodomain structure and the localization of both voltage-gated sodium channel 1.5 (NaV1.5) and Cx43 to ICDs. Despite the loss of NaV1.5 at ICDs, whole-cell patch clamp electrophysiology did not reveal reductions in Na+ currents but did show reduced Ca2+ and K+ currents in Tmem65 KD cardiomyocytes in comparison to control cells. We conclude that disrupting Tmem65 function results in impaired ICD structure, abnormal cardiac electrophysiology, and ultimately cardiomyopathy.en
dc.description.versionPublished versionen
dc.format.extent18 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 6166 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41467-022-33303-yen
dc.identifier.eissn2041-1723en
dc.identifier.issn2041-1723en
dc.identifier.issue1en
dc.identifier.orcidGourdie, Robert [0000-0001-6021-0796]en
dc.identifier.other10.1038/s41467-022-33303-y (PII)en
dc.identifier.pmid36257954en
dc.identifier.urihttps://hdl.handle.net/10919/121220en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36257954en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subject.meshMyocardiumen
dc.subject.meshMyocytes, Cardiacen
dc.subject.meshAnimalsen
dc.subject.meshMiceen
dc.subject.meshConnexin 43en
dc.subject.meshTranscription Factorsen
dc.subject.meshRNA, Small Interferingen
dc.subject.meshNAV1.5 Voltage-Gated Sodium Channelen
dc.titleTmem65 is critical for the structure and function of the intercalated discs in mouse heartsen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2022-09-07en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Emergency Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Emergency Medicine/Emergency Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Emergency Medicine/Emergency Medicine/Secondary Appointment-Emergency Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Emergency Medicine/Secondary Appointment - Emergency Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen
pubs.organisational-groupVirginia Tech/University Research Institutesen
pubs.organisational-groupVirginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

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