# Non-junctional roles of desmosome proteins in the pathogenesis of arrhythmogenic cardiomyopathy

> **NIH NIH R56** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $501,616

## Abstract

PROJECT SUMMARY
Cardiovascular diseases remain the major cause of death in the US. Recent advances in reprogramming
somatic cells from cardiac patients into induced pluripotent stem cells (iPSCs) enables in vitro modeling of
human cardiac diseases for pathogenic studies and therapeutic screens. Traditionally, weakened desmosome
junctions are considered the main pathogenic mechanism for Arrhythmogenic Cardiomyopathy (AC), caused
by mutations in five desmosome component proteins. Pathological hallmarks of AC are progressive fibro-fatty
replacement of cardiomyocytes (CMs) with increased CM apoptosis primarily in the RV, leading to sudden
death in the young. We have established a novel method to induce adult-like, fatty acid oxidation-dominant
metabolism of primitive CMs derived from iPSCs (iPSC-CMs) and established the first metabolic maturation-
based in vitro cardiac disease model for elucidation of novel pathogenic insights for human AC (Nature, 2013).
We showed that abnormal PPARγ activation after normal PPARα-mediated metabolic maturation in AC CMs
resulted in exaggerated lipogenesis, apoptosis, sodium channel deficits and defective Ca2+ handling in CMs
with desmosome mutations, recapitulating the pathological signatures of AC hearts. Using our AC model and
samples from pathological human AC hearts, we show here that plakoglobin is a key component of Insulin-p85
metabolic signaling complex. Desmosome mutations lead to faster plakoglobin degradation, reduce PI3K/Akt
activation, and hyperactivate GSK3β, which downregulate a microRNA (miR) cluster leading to subsequent
abnormal PPARγ activation and CM apoptosis. Importantly, we used genetic and cellular methods to confirm
the clinically relevance of our pathogenic pathways in human AC hearts and in mouse models of AC. We
propose here to further elucidate the dysregulated and non-junctional signaling networks caused by
plakoglobin deficits, to study how plakophilin-2 deficits deregulate additional signaling pathways, and to find
clinically safe therapeutic agents for treating AC using both in vitro iPSC-CM based models and mouse models
of AC.

## Key facts

- **NIH application ID:** 10705361
- **Project number:** 1R56HL161741-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** HUEI-SHENG Vincent CHEN
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $501,616
- **Award type:** 1
- **Project period:** 2022-09-22 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10705361

## Citation

> US National Institutes of Health, RePORTER application 10705361, Non-junctional roles of desmosome proteins in the pathogenesis of arrhythmogenic cardiomyopathy (1R56HL161741-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10705361. Licensed CC0.

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