Increased Nuclear Susceptibility to Mechanical Stress in Phospholamban R14del Cardiomyopathy: A New Perspective on Disease Heterogeneity

PLN R14del cardiomyopathy is linked to increased nuclear susceptibility to mechanical stress, with impaired nuclear calcium handling and elevated nuclear bodies in mechanically loaded hiPSC-cardiomyocytes.

• Why it matters: Clinical severity in PLN R14del cardiomyopathy varies widely and is not fully explained by sarcoplasmic reticulum calcium handling, leaving nuclear mechanosensing and calcium signalling under load unclear.
• What they did: hiPSC-CMs carrying PLN R14del, an isogenic control, and wildtype controls were exposed to cyclic stretch and substrates of 10–20 kPa or 65–85 kPa, with nuclear morphology, nuclear bodies, traction force microscopy, and immunofluorescence readouts. Patient tissues were analyzed under mechanical loading at left ventricular assist device implantation and unloading at heart transplantation, with living myocardial slices from a PLN R14del patient tested under overloading versus physiological loading.
• The result: Under mechanical stress, PLN R14del cells showed impaired mechanotransduction, elevated nuclear bodies, a strain-avoidance response that failed to prevent apoptosis, and nuclear abnormalities in patient myocardial slices and biopsies that normalized with relative mechanical unloading.