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

The phospholamban (PLN) 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 Δ/+). We show that DWORF -/- mice maintained a normal left-ventricular ejection fraction (LVEF) during ageing and no difference with WT control mice could be observed up to 20 months of age. R14 Δ/+ mice maintained a normal cardiac function until 12 months of age, but at 18 months of age LVEF was significantly reduced as compared with WT mice. Absence of DWORF did not accelerate the R14 Δ/+-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 R14 Δ/+ mutation. Together, these results demonstrate that absence of DWORF does not accelerate nor 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 ageing.