Cardiac remodeling pathways do not accelerate disease onset and severity in a mouse model of PLN-R14del cardiomyopathy

Oct 9, 2025Scientific reports

Heart muscle changes do not speed up disease start or severity in a mouse model of PLN-R14del heart disease

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Abstract

At 6 weeks, transverse aortic constriction (TAC) induced increased left ventricular wall thickness and reduced ejection fraction in both wild-type and PLN-R14del mice.

PLN-R14del is associated with ventricular arrhythmias and dilated cardiomyopathy in carriers.
The development of the disease shows high variability, suggesting the influence of additional disease triggers.
TAC resulted in comparable hypertrophic and fibrotic responses in both PLN-R14del and wild-type mice.
Activation of cardiac remodeling and stress pathways was observed in response to TAC, but no PLN-R14del-specific sarco-endoplasmic reticulum malformation was triggered.
The findings indicate that common cardiac stress pathway activation alone may not be sufficient to accelerate PLN-R14del cardiomyopathy onset.

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PLN-R14del is a pathogenic Phospholamban (PLN) gene variant, characterized by ventricular arrhythmias and dilated cardiomyopathy in heterozygous carriers. Disease development is highly heterogeneous, indicating involvement of additional disease triggers, influencing both the onset and severity of the disease. A heterozygous PLN-R14del mouse model (R14) was used to investigate whether cardiac pressure induced by transverse aortic constriction (TAC), could accelerate disease onset.Wild-type littermates and sham operated animals were used as controls. surgery. At 6-weeks, both TAC groups exhibited increased in left ventricular wall thickness, ventricular and atrial weights, and reduced ejection fraction, with comparable hypertrophic and fibrotic responses. Furthermore, differential gene expression showed comparable activation of cardiac remodeling and stress pathways, and changes in metabolic genes expression. Importantly, TAC did not induce sarco-endoplasmic reticulum malformation in R14mice, suggesting that general cardiac stress and remodeling pathways are insufficient to trigger PLN-R14del cardiomyopathy .In conclusion, TAC induced pressure overload provoked robust cardiac remodeling with activation of common stress pathways in young adult WT and R14mice. It did not trigger PLN-R14del-specific sarco-endoplasmic malformation or accelerate disease progression. These findings imply that activation of common cardiac stress pathways alone may be insufficient to accelerate the onset of PLN-R14del cardiomyopathy in early adulthood. Δ/+ Δ/+ Δ/+

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Cardiac remodeling pathways do not accelerate disease onset and severity in a mouse model of PLN-R14del cardiomyopathy

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