ArticleCardiovascular research2025
In PLN-R14del mice, SR structure restoration, rather than calcium cycling, is the dominant effector of PLN-ASO treatment.
Article in Cardiovascular research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Phosphoproteomics distinguishes disease-specific mechanisms for human phospholamban cardiomyopathy reversible by RNA therapy.Signal transduction and targeted therapy · 2026Article
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Abstract
aimsPhospholamban (PLN) acts as an inhibitory regulator of calcium uptake in the sarco-/endoplasmic reticulum (SR) of cardiomyocytes. The pathogenic variant, PLN-R14del, leads to dilated and/or arrhythmogenic cardiomyopathy. Previous studies demonstrated that PLN-targeting antisense oligonucleotides (ASOs) can mitigate disease progression in mice. However, it remains unclear whether the protective effects of PLN-ASO therapy are due to improved calcium homeostasis or via reduction of abnormal PLN-SR clusters, a hallmark of this disease. METHODS AND
resultsHomozygous PLN-R14del (R14Δ/Δ) mice were randomized to injections with various doses of PLN-ASO (3, 7, 15, or 25 mg/kg) or a scrambled control. Consistent with previous findings, R14Δ/Δ mice exhibited severe cardiac dysfunction, myocardial fibrosis, and aberrant SR clusters by 7 weeks of age. ASO-treated R14Δ/Δ mice displayed a dose-dependent preservation of cardiac function with diminished remodelling and extended lifespan. Correspondingly, abnormal PLN-SR clustering was diminished by ASO therapy in a dose-dependent manner, and SR structure returned to a normal state. Calcium dynamics were investigated separately on isolated cardiomyocytes from treated mice. In wild-type (WT) mice, ASO (25 mg/kg) mediated PLN depletion significantly enhanced calcium and contractile dynamics, confirming effective target engagement. In R14Δ/Δ cardiomyocytes, however, ASO treatment showed limited effects on calcium dynamics. Calcium transient decay and sarcomeric shortening were already enhanced in R14Δ/Δ cardiomyocytes compared to WT, suggesting a partial loss of the PLN-R14del calcium inhibitory function. This pre-existing acceleration of calcium dynamics likely accounts for the limited impact of ASO therapy on calcium regulation in R14Δ/Δ mice.
conclusionsPLN-ASO treatment demonstrated a dose-dependent restoration of SR organization and a concomitant increase in lifespan in PLN-R14del mice. The enhanced SR calcium uptake in PLN-R14del mice suggests a partial loss of inhibitory function, limiting ASO therapy's effects on calcium dynamics. This implies that PLN-ASO therapy acts predominantly via restoration of SR structure in PLN-R14del cardiomyopathy.
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