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

Autor: Teng ACT; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. Allen.Teng@utoronto.ca.; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada. Allen.Teng@utoronto.ca., Gu L; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada., Di Paola M; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada., Lakin R; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada., Williams ZJ; The Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute at Virginia Tech. Carilion, Roanoke, VA, 24016, USA.; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Roanoke, VA, 24016, USA., Au A; Institute of Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada., Chen W; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada., Callaghan NI; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada.; Institute of Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada., Zadeh FH; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada.; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada., Zhou YQ; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada.; Institute of Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada., Fatah M; The Labatt Family Heart Centre (Dept. of Pediatrics) and Translational Medicine, The Hospital for Sick Children & Research Institute, University of Toronto, Toronto, ON., M5G 1X8, Canada., Chatterjee D; The Labatt Family Heart Centre (Dept. of Pediatrics) and Translational Medicine, The Hospital for Sick Children & Research Institute, University of Toronto, Toronto, ON., M5G 1X8, Canada., Jourdan LJ; The Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute at Virginia Tech. Carilion, Roanoke, VA, 24016, USA.; Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA., Liu J; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada., Simmons CA; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada.; Institute of Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada., Kislinger T; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G 1L7, Canada., Yip CM; Institute of Biomedical Engineering, Faculty of Applied Science and Engineering, University of Toronto, Toronto, ON, M5S 3G9, Canada.; Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada., Backx PH; Department of Biology, York University, Toronto, ON, M3J 1P3, Canada., Gourdie RG; The Center for Heart and Reparative Medicine, Fralin Biomedical Research Institute at Virginia Tech. Carilion, Roanoke, VA, 24016, USA.; Virginia Tech Carilion School of Medicine, Roanoke, VA, 24016, USA.; Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24060, USA., Hamilton RM; The Labatt Family Heart Centre (Dept. of Pediatrics) and Translational Medicine, The Hospital for Sick Children & Research Institute, University of Toronto, Toronto, ON., M5G 1X8, Canada., Gramolini AO; Department of Physiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON, M5S 1A8, Canada. Anthony.Gramolini@utoronto.ca.; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G 1M1, Canada. Anthony.Gramolini@utoronto.ca.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Oct 18; Vol. 13 (1), pp. 6166. Date of Electronic Publication: 2022 Oct 18.
DOI: 10.1038/s41467-022-33303-y
Abstrakt: 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 Ca 2+ 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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