September 22, 2026Circulation Research
Calpain-Dependent Protein Degradation Contributes to CASQ2-R33Q CPVT
Key result
Calpain inhibition reduces VT in Casq2 mutant mice by restoring CASQ2 and TRDN proteins.
Why the study?
The mechanisms underlying the reduction of couplon proteins and their contribution to CPVT in CASQ2-R33Q mutation are incompletely understood.
Key Points
- Investigate the proteolytic mechanisms causing the loss of calcium-handling couplon proteins and triggered ventricular arrhythmias in CASQ2-R33Q catecholaminergic polymorphic ventricular tachycardia.
- Evaluated endoplasmic reticulum stress, the unfolded protein response, and proteolytic pathways using proteomics in homozygous Casq2 R33Q/R33Q mice.
- Tested pharmacological inhibitors of the proteasome, autophagy, and calpain in isolated neonatal cardiomyocytes and adult mutant mice.
- Assessed triadin (TRDN) as a direct calpain substrate and restored TRDN expression in vivo using modified RNA and adeno-associated viral vectors.
- Calpain directly degraded TRDN prior to CASQ2 loss, whereas proteasome and autophagy inhibition partially restored CASQ2 but failed to rescue TRDN.
- Calpain inhibition normalized CASQ2 and TRDN abundance, reduced triggered electrical activity in isolated cardiomyocytes, and prevented ventricular tachycardia episodes in mutant mice.
- Exogenous TRDN replacement via modified RNA or viral delivery restored CASQ2 levels in vivo, confirming an upstream driver role for TRDN destabilization.
Structured PICO
P
Population
Homozygous mouse model Casq2 R33Q/R33Q and neonatal cardiomyocytes
I
Intervention
Calpain inhibition, proteasome inhibition, autophagy inhibition, and TRDN overexpression (via modified RNA or AAV vector)
C
Comparator
Untreated Casq2 R33Q/R33Q mice and cardiomyocytes
O
Outcome
CASQ2 and TRDN protein levels, triggered activity in isolated cardiomyocytes, and ventricular tachycardia episodes in vivosurrogate
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Our results identify protein degradation as an important mechanism contributing to the development of this form of CPVT, and show that calpain could represent a new therapeutic target.”
“activates various cellular degradation mechanisms that reduce the levels of essential proteins in the molecular complex responsible for regulating calcium release inside cardiomyocytes.”
“This abnormality, explains Dr. Lara-Pezzi, “activates various cellular degradation mechanisms that reduce the levels of essential proteins in the molecular complex responsible for regulating calcium release inside cardiomyocytes.””
Implication
Calpain-dependent TRDN degradation is a key pathogenic event in CASQ2-R33Q CPVT, and its inhibition reduces ventricular tachycardia in a mouse model.
Abstract
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease associated with cardiac arrest in children and young adults. The recessive form of CPVT is caused by loss-of-function mutations in the genes encoding CASQ2 and TRDN , which, together with JCTN , regulate the release of calcium ions from the sarcoplasmic reticulum through the RyR2 (ryanodine receptor). The CASQ2 R33Q mutation causes calcium mishandling and ventricular tachycardia through triggered activity. The homozygous mouse model Casq2 R33Q/R33Q closely replicates the clinical phenotype of patients with CPVT. In this model, CASQ2 (calsequestrin 2), TRDN (triadin), and JCTN (junctin) levels are markedly reduced; however, the mechanisms underlying this reduction and their contribution to CPVT are incompletely understood. METHODS: We used a combination of proteomics, animal models, and experimental methods to identify the molecular mechanisms responsible for the decrease of couplon proteins in Casq2 R33Q/R33Q mice and to explore their functional contribution to the disease. RESULTS: Casq2 R33Q/R33Q hearts showed activation of endoplasmic reticulum stress, the unfolded protein response, and alterations in major proteolytic pathways. Inhibition of the proteasome or autophagy in neonatal cardiomyocytes and adult mice partially restored CASQ2 but not TRDN levels, suggesting distinct degradation mechanisms. In contrast, calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2 R33Q/R33Q mice. Biochemical assays showed that TRDN is a direct calpain substrate. TRDN degradation preceded CASQ2 loss, and TRDN overexpression using modified RNA in cardiomyocytes or an adeno-associated viral vector in vivo increased CASQ2 levels in mutant mice, supporting an upstream role for TRDN destabilization. CONCLUSIONS: Couplon protein loss in CPVT associated with CASQ2-R33Q is mediated by coordinated but distinct proteolytic pathways, with calpain-dependent TRDN degradation representing a key pathogenic event that promotes CASQ2 destabilization and arrhythmogenesis.
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Cite This Study
Ramos-Hernández et al. (2026) studied Catecholaminergic polymorphic ventricular tachycardia (CPVT). Calpain inhibition and TRDN overexpression was evaluated on CASQ2 and TRDN protein levels, triggered activity, and ventricular tachycardia episodes. Calpain inhibition restored CASQ2 and TRDN protein levels, decreased triggered activity in isolated cardiomyocytes, and reduced ventricular tachycardia episodes in vivo in Casq2 R33Q/R33Q mice.