Deletion of DWORF does not affect cardiac function in aging and in PLN-R14del cardiomyopathy

Feb 9, 2024American journal of physiology. Heart and circulatory physiology

Removing DWORF does not change heart function in aging or in a specific inherited heart disease

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Abstract

Deletion of DWORF does not accelerate cardiomyopathy caused by the PLN-R14del gene variant in mice.

The pathogenic gene variant p.Arg14del in phospholamban is linked to cardiomyopathy and severe heart failure.
DWORF can counteract the effects of PLN, and its overexpression delays disease progression in PLN-R14del mice.
In wild-type and PLN-R14del mice lacking DWORF, normal left ventricular ejection fraction was maintained up to 20 months.
R14 mice showed a significant reduction in left ventricular ejection fraction by 18 months compared to wild-type mice.
Absence of DWORF did not worsen heart function, cardiac remodeling, or fibrosis related to the PLN-R14del mutation.
Changes in DWORF expression are unlikely to explain the variability seen in PLN-R14del cardiomyopathy among patients.

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The phospholamban () pathogenic gene variant p.Arg14del causes cardiomyopathy, which is characterized by perinuclear PLN protein clustering and can lead to severe heart failure (HF). Elevated expression of dwarf open reading frame (DWORF), a protein counteracting the function of PLN in the sarcoplasmic reticulum (SR), can delay disease progression in a PLN-R14del mouse model. Here, we evaluated whether deletion of DWORF (DWORF) would have an opposite effect and accelerate age-dependent disease progression in wild-type (WT) mice and mice with a pathogenic PLN-R14del allele (R14). We show that DWORFmice maintained a normal left ventricular ejection fraction (LVEF) during aging and no difference with WT control mice could be observed up to 20 mo of age. R14mice maintained a normal cardiac function until 12 mo of age, but at 18 mo of age, LVEF was significantly reduced as compared with WT mice. Absence of DWORF did neither accelerate the R14-induced reduction in LVEF nor enhance the increases in gene expression of markers related to cardiac remodeling and fibrosis and did not exacerbate cardiac fibrosis caused by the R14mutation. Together, these results demonstrate that absence of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, our data indicate that DWORF appears to be dispensable for cardiac function during aging.Although DWORF overexpression significantly delayed heart failure development and strongly prolonged life span in PLN-R14del mice, the current study shows that deletion of DWORF does not accelerate or exacerbate PLN-R14del cardiomyopathy in mice harboring the pathogenic R14del allele. In addition, DWORF appears to be dispensable for cardiac function during aging. Changes in DWORF gene expression are therefore unlikely to contribute to the clinical heterogeneity observed in patients with PLN-R14del cardiomyopathy. PLN -/-Δ/+ -/-Δ/+ Δ/+ Δ/+ NEW & NOTEWORTHY

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Deletion of DWORF does not affect cardiac function in aging and in PLN-R14del cardiomyopathy

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