DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters

Nov 13, 2023Circulation research

DWORF may extend life span in a heart disease mouse model by reducing abnormal calcium storage clusters

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Abstract

Restoration of DWORF expression in PLN-R14del mice increased life span by more than 2-fold (from 8 to 18 weeks).

The p.Arg14del variant of the phospholamban gene is associated with severe heart failure due to calcium handling defects and PLN aggregation.
DWORF may counteract the pathological effects of PLN by enhancing calcium handling in cardiac cells.
In R14DWORF mice, DWORF overexpression delayed cardiac fibrosis and the progression of heart failure.
Sarcoplasmic reticulum calcium reuptake and relaxation were enhanced in R14 cardiomyocytes, with no additional benefits from DWORF overexpression.
DWORF overexpression reduced the formation of large pathogenic PLN clusters, which are linked to disorganized sarco/endoplasmic reticulum.
Disorganized sarco/endoplasmic reticulum contributes to cardiomyocyte death and replacement fibrosis in PLN-R14del cardiomyopathy.

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BACKGROUND: The p.Arg14del variant of the(phospholamban) gene causes cardiomyopathy, leading to severe heart failure. Calcium handling defects and perinuclear PLN aggregation have both been suggested as pathological drivers of this disease. Dwarf open reading frame (DWORF) has been shown to counteract PLN regulatory calcium handling function in the sarco/endoplasmic reticulum (S/ER). Here, we investigated the potential disease-modulating action of DWORF in this cardiomyopathy and its effects on calcium handling and PLN aggregation. PLN

METHODS: We studied a PLN-R14del mouse model, which develops cardiomyopathy with similar characteristics as human patients, and explored whether cardiac DWORF overexpression could delay cardiac deterioration. To this end, R14(homozygous PLN-R14del) mice carrying the DWORF transgene (R14DWORF[R14mice carrying the DWORF transgene]) were used. Δ/Δ Δ/Δ Tg Δ/Δ

RESULTS: DWORF expression was suppressed in hearts of R14mice with severe heart failure. Restoration of DWORF expression in R14mice delayed cardiac fibrosis and heart failure and increased life span >2-fold (from 8 to 18 weeks). DWORF accelerated sarcoplasmic reticulum calcium reuptake and relaxation in isolated cardiomyocytes with wild-type PLN, but in R14cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14and R14DWORF. Rather, DWORF overexpression delayed the appearance and formation of large pathogenic perinuclear PLN clusters. Careful examination revealed colocalization of sarcoplasmic reticulum markers with these PLN clusters in both R14mice and human p.Arg14del PLN heart tissue, and hence these previously termed aggregates are comprised of abnormal organized S/ER. This abnormal S/ER organization in PLN-R14del cardiomyopathy contributes to cardiomyocyte cell loss and replacement fibrosis, consequently resulting in cardiac dysfunction. Δ/Δ Δ/Δ Δ/Δ Δ/Δ Δ/Δ Tg Δ/Δ

CONCLUSIONS: Disorganized S/ER is a major characteristic of PLN-R14del cardiomyopathy in humans and mice and results in cardiomyocyte death. DWORF overexpression delayed PLN-R14del cardiomyopathy progression and extended life span in R14mice, by reducing abnormal S/ER clusters. Δ/Δ

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DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum Clusters

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