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Cardiomyocyte-specific lamin A re-expression via AAV-Lmna/DJ8 ameliorates cardiac dysfunction in Lmna⁻/⁻ mice

ABSTRACT: Mutations in LMNA, which encodes the nuclear envelope protein lamin A/C, cause laminopathies that frequently present as dilated cardiomyopathy (DCM). We investigated whether re-expression of lamin A in cardiomyocytes can rescue the severe phenotype of Lmna⁻/⁻ mice. An adeno-associated virus vector expressing wild-type Lmna (AAV-Lmna/DJ8) was administered intrathoracically to neonatal mice. Three weeks after injection, treated Lmna⁻/⁻ mice exhibited robust cardiac Lmna mRNA induction and nuclear localization of lamin A protein, reflecting efficient cardiotropic gene delivery. Compared with PBS treatment, AAV-Lmna/DJ8 treatment promoted body weight maintenance, improved left ventricular systolic function, and significantly prolonged survival in Lmna⁻/⁻ mice. To explore the underlying mechanisms, we performed single-nucleus RNA sequencing of cardiomyocytes from wild-type mice, PBS-treated Lmna⁻/⁻ mice, and AAV-Lmna/DJ8–treated Lmna⁻/⁻ mice. AAV-mediated lamin A re-expression shifted the cardiomyocyte transcriptome toward the wild-type profile, and restored oxidative phosphorylation–related gene programs, which were diminished in untreated Lmna⁻/⁻ mice. These findings demonstrate that targeted re-expression of Lmna ameliorates cardiac dysfunction in Lmna⁻/⁻ mice and highlight the therapeutic potential of LMNA gene replacement for laminopathy-associated cardiomyopathy.

ORGANISM(S): Mus musculus

PROVIDER: GSE319519 | GEO | 2026/05/12

REPOSITORIES: GEO

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Interplay of stress responses underlying the development of LMNA cardiomyopathy

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TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Project description:• Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA-seq, ATAC-seq, protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEAD1 by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R- LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA-mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from DCM patients with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

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Lamin C supplementation as therapeutic target for treatment of Lmna Dilated Cardiomyopathy (DCM) and risk of Lamin A toxicity

Project description:Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease, which ultimately results in heart failure (HF). Pathological genetic variants in LMNA cause DCM, which currently lacks specific treatment. Perturbing candidates related to dysregulated pathways have shown to ameliorate LMNA DCM, but their long-term efficacy as potential therapeutic targets is unknown. Here, we evaluated 14 potential candidates including Lmna gene products, key signaling pathways, calcium handling, proliferation regulators and Lamin interacting proteins, in a cardiac-specific Lmna DCM model. The candidates with improved cardiac function were further assessed through survival analysis. After comparing cardiac function, marker gene expression, Tgfβ signaling pathway activation, fibrosis, inflammation, proliferation, and DNA damage, we uncovered that restored cardiac function significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Interestingly, Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. In addition to Sun1 shRNA, perturbing the interaction between the nucleoskeleton and cytoskeleton via the KASH domain of Nesprin1 also effectively suppressed Lmna DCM. In contrast, Lamin A supplementation did not rescue long term survival and may impart a detrimental cardiotoxicity risk. Furthermore, transcriptome profiling was used to compare the differences between Lamin A and Lamin C treatment. Mechanistically, we identified that this lapse was attributed to a dose-dependent toxicity of Lamin A, which was independent of its maturation. This study highlights the potential for advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.

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