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Nuclear envelope rupture in cardiomyocytes orchestrates early transcriptomic changes and immune activation in LMNA-DCM that are reversed by LINC complex disruption

ABSTRACT: Mutations in the LMNA gene, which encodes the nuclear envelope (NE) proteins lamins A/C, cause dilated cardiomyopathy (LMNA-DCM) and other diseases. The pathogenic mechanisms for LMNA-DCM remain poorly understood, limiting current treatment options and leading to high mortality amongst patients. We developed a mouse model with inducible, cardiomyocyte-specific Lmna deletion and performed comprehensive transcriptomic analyses (bulk, single-nucleus, and spatial) across disease progression. We identified key disease-driving genes involved in cellular responses to DNA damage, cytosolic pattern recognition receptor signaling, and innate immunity that originated from two disease-specific cardiomyocyte subpopulations. Spatial mapping revealed aberrant interactions between these cardiomyocytes, fibroblasts, and immune cells, contributing to tissue-wide transcriptional changes. Using mice with inducible, cardiomyocyte-specific disruption of the LINC complex, which transmits cytoskeletal forces to the nucleus, we demonstrated that reducing NE rupture corrected ~50% of misregulated genes and dramatically improved cardiac function and survival in the LMNA-DCM mouse model. These findings suggest that loss of nuclear integrity in Lmna-depleted cardiomyocytes triggers cytosolic DNA sensing and maladaptive cell-cell communication with fibroblasts and immune cells, promoting fibrosis and inflammation characteristic of LMNA-DCM.

ORGANISM(S): Mus musculus

PROVIDER: GSE307910 | GEO | 2026/09/08

REPOSITORIES: GEO

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Nuclear envelope rupture causes RNA polymerase loss in LMNA cardiomyopathy

Project description:Localized rupture of the nuclear envelope has been reported in various pathologies, including cancer, neurodegenerative disease, myocardial infarction, as well as dilated cardiomyopathy caused by Lamin A/C gene mutations (LMNA-DCM). Whether and how nuclear rupture contributes to disease remains unclear. Here, we report that nuclear rupture causes global transcriptional deficiency in a mouse model of LMNA-DCM. We observed that ruptured nuclei lost chromatin-bound RNA polymerase II, leading to downregulation of numerous genes essential for cardiomyocyte structure and function. Notably, over one third of ruptured nuclei resealed and regained transcription. Resealing involved the ESCRT-III membrane remodeling complex and was cardioprotective, as its blockade increased rupture frequency and accelerated cardiomyopathy. However, resealing was ineffective: resealed nuclei re-ruptured at twice the resealing rate and ten-fold faster than the de novo rupture rate. A mathematical model predicted a steady accumulation of ruptured nuclei despite ongoing resealing. Consistently, a human LMNA-mutant heart contained numerous ruptured nuclei at the time of disease presentation. These findings link nuclear rupture to organ deterioration through global transcriptional deficiency and suggested rupture repair as a critical modifier of nuclear rupture-associated conditions.

2026-04-03 | GSE325163 | GEO

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.

2024-08-11 | GSE240745 | GEO

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.

2023-03-06 | GSE190977 | GEO

Unraveling Diabetic Cardiomyopathy (DCM): The Critical Role of the Yap–miR-22-3p–Sirt1 axis in the Pathogenesis of DCM

Project description:Background: Diabetic cardiomyopathy (DCM), characterized by myocardial hypertrophy and myocardial fibrosis, is a severe complication of diabetes. Yes-associated protein (Yap) activation contributes to myocardial remodeling and cardiac dysfunction. This study investigated the role of Yap and its molecular mechanism in DCM. Methods: Yap expression was assessed in mice with type 2 diabetes mellitus (T2DM) and high glucose (HG) + insulin-treated neonatal rat cardiomyocytes (NRCMs). Adeno-associated virus transfection, siRNA transfection, and a transgenic mouse model were used to manipulate Yap and sirtuin 1 (Sirt1) expression in vivo and in vitro. RNA sequencing, differential gene analysis, and miRNA sequencing were used to identify downstream targets of Yap and the underlying mechanisms. Functional assays were used to evaluate cardiomyocyte hypertrophy and fibrosis through molecular markers, cell morphology, and echocardiography. Results: Yap expression was increased in HG + insulin-treated NRCMs and in the hearts of mice with T2DM, thereby promoting myocardial hypertrophy and fibrosis. Yap inhibition reduced the cardiomyocyte cross-sectional area, collagen deposition, and the levels of the hypertrophy markers atrial natriuretic peptide and β-myosin heavy chain. RNA sequencing identified Sirt1 as a downstream target of Yap. Bioinformatic analysis suggested that Yap positively regulates miR-22-3p, which inhibits Sirt1. Yap inhibition increased Sirt1 expression, mitigating myocardial remodeling. Conversely, Sirt1 knockdown reversed the protective effects of Yap inhibition, restoring hypertrophy and fibrosis. Conclusion: Yap promotes DCM progression by increasing miR-22-3p expression and suppressing Sirt1 expression. Targeting the Yap–miR-22-3p–Sirt1 axis might represent a novel therapeutic strategy for DCM, thereby improving myocardial structure and function.

2026-02-28 | GSE290303 | GEO

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

Project description: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.

2026-05-12 | GSE319519 | GEO

Project description:LMNA-Related DCM involves cardiomyocyte dysfunction resulting in heart failure or sudden death. It is caused by LMNA mutations encoding Lamin A/C defects involved in nuclear integrity and gene expression. To investigate possible mechanisms, we used iPSC derived from a LMNA c.357-2A>G Patient and her unaffected sister. We differentiated iPSC and conducted scRNA-seq for 4 Patient and 8 Control samples across seven time points from Day 0 to 30. Using a comprehensive bioinformatics workflow, we identified 110,521 high-quality cells and complex heterogeneity: ten main cell types, possible subtypes, and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes and Epicardium-Derived Cells (EPDC). By comparative analyses, we found differentially expressed genes (DEG) and enrichment supporting pathway dysregulation for ZNF genes and RNA polymerase II transcription in Pluripotent cells; BMP4 and TGF Beta/BMP signaling, sarcomere genes and cardiogenesis, CDH2 and EMT in Cardiomyocytes; LMNA and epigenetic regulation and DDIT4 and mTORC1 signaling in EPDC. In addition, top DEG included XIST, six imprinted genes, and gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our evidence supports disruption of epigenomic developmental programs in LMNA-Related DCM and also demonstrates current challenges of LMNA disease modeling using Patient-derived iPSC.

2024-09-03 | GSE269705 | GEO

Unraveling Diabetic Cardiomyopathy (DCM): The Critical Role of the Yap–miR-22-3p–Sirt1 axis in the Pathogenesis of DCM [miRNA-seq]

2026-06-01 | GSE290829 | GEO

Simtuzumab Attenuates Loxl2-Mediated Extracellular Matrix Remodeling and Preserves Cardiac Function in LMNA Mutation-Induced Dilated Cardiomyopathy

Project description:Background | Dilated cardiomyopathy (DCM) caused by LMNA mutations is a severe cardiac condition marked by arrhythmias, contractile dysfunction, and excessive myocardial fibrosis, which collectively impair left ventricular function and increase the risk of heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis has impeded the development of therapies. Methods | Here, we employed induced pluripotent stem cells (hiPSCs) derived from a patient carrying a LMNA point mutation (c.665A>C, p.His222Pro), alongside a murine model carrying the same mutation, to investigate the functional and molecular abnormalities driving DCM. Results | We demonstrated that LMNA patient-derived cardiomyocytes (hiPSC-CMs) and engineered heart tissues (hiPSC-EHTs) exhibited elevated diastolic calcium levels and reduced sensitivity to external calcium, respectively, as well as hypocontractility. These cells also displayed nuclear shape abnormalities in 2D and 3D, a hallmark of LMNA-associated DCM, associated with disrupted chromosome spatial organization and altered gene expression profiles. Transcriptomic analysis revealed dysregulation of extracellular matrix remodeling and significant upregulation of Loxl2 in mutated hiPSC-CMs, hiPSC-EHTs, and mice. Treatment with Simtuzumab, a Loxl2 inhibitor, effectively prevented cardiac dysfunction and fibrosis in vivo. Conclusion | Taken together, our findings underscore the crucial role of Loxl2 as a therapeutic target and suggest that its inhibition could be a promising strategy to preserve cardiac function in LMNA-associated DCM.

2026-01-30 | GSE312730 | GEO

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2025-03-01 | GSE182219 | GEO

Targetting interleukins and chemokine mediated signalling pathway in DCM caused by LMNA 289A>G

Project description:Lamins are type V intermediate filament proteins underlying the inner nuclear membrane which provide structural rigidity to the nucleus, tether the chromosomes and maintain nuclear homeostasis. Studies have identified developmentally regulated regions of the genome that are dynamically associated with the nuclear lamina. A large number of mutations in LMNA gene encoding lamin A/C results in a wide array of human diseases, collectively termed as laminopathies. Dilated Cardiomyopathy (DCM) is one such cardiovascular disease which is associated with systolic dysfunction of left or both ventricles leading to cardiac arrhythmia culminating into myocardial infarction. In this work, we have unravelled the gene expression by RNA Sequencing analysis in mouse myoblast cell line in the context of the missense mutation LMNA 289A>G (Lys97Glu) that is found in DCM afflicted patients with severe symptoms.

2022-06-26 | GSE206759 | GEO

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