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DWORF Extends Life Span in a PLN-R14del Cardiomyopathy Mouse Model by Reducing Abnormal Sarcoplasmic Reticulum
Nienke M Stege1, Tim R Eijgenraam1, Vivian Oliveira Nunes Teixeira1
1Department of Cardiology, University Medical Center Groningen, University of Groningen, the Netherlands (N.M.S., T.R.E., V.O.N.T., A.M.F., E.M.S., R.A.d.B., H.H.W.S.).
Insights
Dwarf open reading frame (DWORF) overexpression in phospholamban (PLN)-R14del mice delayed heart failure progression and doubled lifespan. DWORF reduced abnormal sarcoplasmic reticulum clusters, a key feature of this cardiomyopathy.
Area of Science:
- Cardiology
- Molecular Biology
- Genetics
Background:
- The phospholamban (PLN) p.Arg14del variant causes severe cardiomyopathy and heart failure.
- Defects in calcium handling and PLN aggregation are implicated in disease pathology.
- Dwarf open reading frame (DWORF) influences PLN's calcium handling role in the sarco/endoplasmic reticulum (S/ER).
Purpose of the Study:
- To investigate DWORF's disease-modulating effects in PLN-R14del cardiomyopathy.
- To assess DWORF's impact on calcium handling and PLN aggregation.
- To explore DWORF as a therapeutic target for PLN-related heart failure.
Main Methods:
- Studied a PLN-R14del mouse model (R14Δ/Δ) with cardiac DWORF transgene expression (R14Δ/ΔDWORFTg).
- Assessed cardiac function, fibrosis, lifespan, and S/ER calcium handling.
- Examined PLN aggregation and S/ER organization in cardiomyocytes.
Main Results:
- DWORF suppressed in R14Δ/Δ mice hearts with severe failure.
- Restored DWORF expression delayed fibrosis, heart failure, and >2-fold increased lifespan (8 to 18 weeks).
- DWORF enhanced S/ER calcium reuptake in wild-type, but not R14Δ/Δ cardiomyocytes; it delayed pathogenic perinuclear PLN cluster formation, revealing these as disorganized S/ER.
Conclusions:
- Disorganized S/ER is a hallmark of PLN-R14del cardiomyopathy, leading to cell death.
- DWORF overexpression mitigates PLN-R14del cardiomyopathy progression and extends lifespan by reducing abnormal S/ER clusters.
Background:
The p.Arg14del variant of the PLN (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.
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, R14Δ/Δ (homozygous PLN-R14del) mice carrying the DWORF transgene (R14Δ/ΔDWORFTg [R14Δ/Δ mice carrying the DWORF transgene]) were used.
Results:
DWORF expression was suppressed in hearts of R14Δ/Δ mice with severe heart failure. Restoration of DWORF expression in R14Δ/Δ mice 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 R14Δ/Δ cardiomyocytes, sarcoplasmic reticulum calcium reuptake and relaxation were already enhanced, and no differences were detected between R14Δ/Δ and R14Δ/ΔDWORFTg. 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 R14Δ/Δ mice 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.
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 R14Δ/Δ mice, by reducing abnormal S/ER clusters.
