LMNA gene encodes lamin A/C, ubiquitous proteins of the nuclear envelope. Some mutations of LMNA gene lead to Emery-Dreifuss muscular dystrophy (EDMD) that associates muscular disease and dilated cardiomyopathy (DCM) with conduction and/or rhythm defects. My work aimed at investigating the phenotype and the associated pathomechanisms in heterozygous LmnaΔK32/+ mice (Het), mutation associated with severe EDMD in patients. Het mice do not show any muscle defect. They progressively develop cardiac dysfunction and DCM, and die between 35 and 70 weeks of age. The evolution of DCM is associated with a modulation of cardiac lamin A/C protein level. Before the development of DCM, lamin A/C protein level is 50% lower in Het than Wt hearts, but do not differ between both groups thereafter. The reduced lamin A/C content resulted from K32-lamin degradation via the ubiquitin-proteasome system (UPS). The UPS function is altered in the heart of Het mice. Overexpression of K32-lamin in engineered heart tissue followed by inhibition of the proteasome results in nuclear aggregation of mutant lamin, suggesting a poison peptide effect of these proteins. To conclude, LmnaΔK32/+ mice are the first knock-in Lmna model with cardiac-specific phenotype at the heterozygous state. UPS plays a key role in mutant lamin degradation, limiting its negative impact upon heart tissue. Our data provide evidence for double pathophysiological mechanisms of DCM in LmnadelK32/+ mice: haploinsufficiency is associated with accumulation of a poison peptide
