Microtubule forces drive nuclear damage in LMNA cardiomyopathy

Nuclear homeostasis requires balanced forces between the cytoskeleton and the nucleus. Mutations in LMNA, which encodes lamin A/C, weaken the nuclear lamina, leading to nuclear damage and muscle disease. Disrupting the linker of nucleoskeleton and cytoskeleton (LINC) complex, which connects the cytoskeleton to the nucleus, may ameliorate LMNA-associated cardiomyopathy, yet the cardioprotective mechanism remains unclear. Here we developed an assay to quantify the coupling between cardiomyocyte contraction and nuclear deformation and interrogate its dependence on the nuclear lamina and LINC complex. The LINC complex was mostly dispensable for transferring contractile strain to the nucleus, and its disruption did not rescue elevated nuclear strain in lamin A/C-deficient cardiomyocytes. Instead, LINC complex disruption eliminated the microtubule cage encircling the nucleus. Microtubule disruption prevented nuclear damage and preserved cardiac function in lamin A/C deficiency. Computational modeling revealed that microtubule forces create local stress concentrations that damage lamin A/C-deficient nuclei. These findings identify microtubule-dependent force transmission as a pathological driver and therapeutic target for LMNA cardiomyopathy.