Biophysical Society Thematic Meeting | Canterbury 2023

Towards a More Perfect Union: Multi-Scale Models of Muscle and Their Experimental Validation

Monday Speaker Abstracts

CONNEXIN43 RESTORATION ALLEVIATES END-STAGE ALTERATIONS IN ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA/CARDIOMYOPATHY Farah Sheikh 1 ; Jing Zhang 1 ; Fabian Zanella 1 ; William Bradford 1 ; Kyohei Fujita 1 ; Matthew Ellis 1 ; Ioannis Karakikes 2 ; Robert Lyon 1 ; Valeria Mezzano 1 ; Jason Roberts 3 ; Cassiano Carromeu 1 ; Yusu Gu 1 ; Jody Martin 4 ; Alysson Muotri 1 ; Melvin Scheinman 3 ; Kirk Peterson 1 ; 1 University of California San Diego, La Jolla, CA, USA 2 Stanford University, Palo Alto, CA, USA 3 University of California San Francisco, San Francisco, CA, USA 4 University of Illinois, Chicago, Chicago, IL, USA Reduction of the predominant ventricular gap junction protein, connexin43, is a molecular hallmark that underlies desmosomal mutations/cell-cell junction deficits and arrhythmias associated with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, less is known of the specific role of connexin43 in the end-stage alterations that facilitate myocardial failure and premature death in ARVD/C populations. In this study, we assessed the impact of connexin43 restoration via viral mediated strategies in mouse and human models of ARVD/C harboring end-stage alterations to reveal therapeutic benefits. We show that connexin43 restoration is sufficient to (i) alleviate cardiac dysfunction and prevent arrhythmias as well as prolong lifespan in a severe mouse model of ARVD/C and (ii) rescue cardiomyocyte physiological deficits in ARVD/C human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CM) that encompassed diverse ARVD/C genetics and disease severity. We show that connexin43 restoration facilitates desmosomal gene and protein expression as well as relocalization to the cell junction in ARVD/C mouse hearts and ARVD/C human cardiomyocytes. In conclusion, we highlight that strategies targeted at increasing full-length connexin43 represents a therapeutic avenue to treat broad and diverse ARVD/C populations.

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