Decrypter les mécanismes pathologiques communs de la cardiomyopathies dilatée causée par des mutations dans les gènes LMNA et DMD par analyse génomique

Duchenne muscular dystrophy and laminopathies lead to the development of dilated cardiomyopathy. Due to the molecular similarities between skeletal and cardiac muscles, cardiomyopathies can be associated with neuromuscular disorders. Neuromuscular diseases are a wide-ranging group of diseases that affect peripheral nerves and/or skeletal and cardiac striated muscles. These two genetic disorders arise from gene mutations encoding dystrophin (DMD) and A-type lamins (LMNA), respectively, causing an absence of dystrophin and an alteration of A-type lamins. Dilated cardiomyopathy is primarily characterized by left ventricular enlargement, which leads to reduced cardiac function, heart failure, and sudden cardiac death. The molecular and cellular mechanisms underlying the onset and development of this common cardiomyopathy, caused by these two different mutations, are still poorly understood. Moreover, it remains unclear how proteins present in distinct cellular compartments can lead to a similar cardiac disease. We hypothesized that the absence of dystrophin and mutated A-type lamins disturb mechanotransduction during cardiac contraction due to their interaction within the protein continuum existing between the extracellular environment and nuclear interior and their similar cellular functions. This alteration would lead to aberrant chromatin modulation in response to these signals, leading to disturbed gene expression and cellular signaling. We conducted a comparative study to explore the common pathological mechanisms between dilated cardiomyopathy caused by DMD and LMNA mutations. To achieve this, we used translational tools with cardiomyocytes derived from human induced pluripotent stem cells (hiPSCs-CMs) and murine models relevant to both diseases. Functional impairments were shown in each disease, including cardiac dysfunction, abnormal morphology, and altered calcium handling. Genomic analysis was focused on chromosome distribution, chromatin accessibility, and gene transcription. Our results showed that these mutations lead to chromosome spatial alterations in vitro and were associated with changes in chromatin accessibility in DMD hiPSCs-CMs. Both mutations led to gene transcription dysregulation, commonly related to elastic fiber assembly and MAPK signaling pathway in vitro and with mechanotransduction, mitosis, and ECM organization in vivo. We uncovered Loxl2 as a promising target to prevent cardiac dysfunction in LMNA-DCM and possibly in DMD-DCM. This unique comparative analysis highlights shared biological pathways that could guide common therapeutic strategies, including Loxl2 inhibition treatment. These findings provide critical insights into the complexity of LMNA- and DMD-DCM, paving the way for more effective and common therapeutic approaches.