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LMNA cardiomyopathy, caused by mutations in the LMNA gene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derived LMNA p.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and a LmnaH222P/H222P mouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed that LMNA p.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark of LMNA cardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in both LMNA p.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac function in vivo. Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function in LMNA cardiomyopathy.
Competing Interest Statement
The authors have declared no competing interest.