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

Allen C. T. Teng (), Liyang Gu, Michelle Paola, Robert Lakin, Zachary J. Williams, Aaron Au, Wenliang Chen, Neal I. Callaghan, Farigol Hakem Zadeh, Yu-Qing Zhou, Meena Fatah, Diptendu Chatterjee, L. Jane Jourdan, Jack Liu, Craig A. Simmons, Thomas Kislinger, Christopher M. Yip, Peter H. Backx, Robert G. Gourdie, Robert M. Hamilton and Anthony O. Gramolini ()
Additional contact information
Allen C. T. Teng: University of Toronto
Liyang Gu: Ted Rogers Centre for Heart Research
Michelle Paola: University of Toronto
Robert Lakin: York University
Zachary J. Williams: Fralin Biomedical Research Institute at Virginia Tech. Carilion
Aaron Au: University of Toronto
Wenliang Chen: York University
Neal I. Callaghan: Ted Rogers Centre for Heart Research
Farigol Hakem Zadeh: University of Toronto
Yu-Qing Zhou: Ted Rogers Centre for Heart Research
Meena Fatah: University of Toronto
Diptendu Chatterjee: University of Toronto
L. Jane Jourdan: Fralin Biomedical Research Institute at Virginia Tech. Carilion
Jack Liu: University of Toronto
Craig A. Simmons: Ted Rogers Centre for Heart Research
Thomas Kislinger: University Health Network
Christopher M. Yip: University of Toronto
Peter H. Backx: York University
Robert G. Gourdie: Fralin Biomedical Research Institute at Virginia Tech. Carilion
Robert M. Hamilton: University of Toronto
Anthony O. Gramolini: University of Toronto

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract The 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.

Date: 2022
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DOI: 10.1038/s41467-022-33303-y

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