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SIRT1 Ameliorates Lamin A/C Deficiency-Induced Cardiac Dysfunction by Promoting Mitochondrial Bioenergetics
Zunhui Du1, Yanting Zhou2, Qiheng Li1
1Department of Cardiovascular Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Abstract:
Dilated cardiomyopathy (DCM) is associated with high mortality despite advanced therapies. The LMNA gene encodes lamin A/C and is the second most frequently mutated gene associated with DCM, for which therapeutic options are limited. Here we generated Lmna -/- mice and found they exhibited cardiac dysfunction at the age of 1 month but not at 2 weeks. Proteomics showed down-regulation of mitochondrial function-related pathways in Lmna -/- hearts. Moreover, early injured mitochondria with decreased cristae density and sirtuin 1 (SIRT1) down-regulation were observed in 2-week-old Lmna -/- hearts. Adenoviral overexpression of SIRT1 in lamin A/C knockdown neonatal rat ventricular myocytes improved mitochondrial oxidative respiration capacity. Adeno-associated virus-mediated SIRT1 overexpression alleviated mitochondrial injury, cardiac systolic dysfunction, ventricular dilation, and fibrosis, and prolonged lifespan in Lmna -/- mice. Mechanistically, LMNA maintains mitochondrial bioenergetics through the SIRT1-PARKIN axis. Our results suggest that targeting the SIRT1 signaling pathway is expected to be a novel therapeutic strategy for LMNA mutation-associated DCM.
Insights
Mutations in the LMNA gene cause dilated cardiomyopathy (DCM). Restoring SIRT1 levels in mice with DCM improved mitochondrial function and extended lifespan, suggesting SIRT1 as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Genetic Diseases
Background:
- Dilated cardiomyopathy (DCM) carries a high mortality rate, with limited therapeutic options for patients.
- Mutations in the LMNA gene, encoding lamin A/C, are a frequent cause of inherited DCM.
Purpose of the Study:
- To investigate the role of LMNA in cardiac function and mitochondrial health.
- To explore the therapeutic potential of targeting the SIRT1 pathway in LMNA-associated DCM.
Main Methods:
- Generation and analysis of Lmna knockout (Lmna-/-) mice.
- Proteomic analysis of Lmna-/- hearts to identify dysregulated pathways.
- In vitro studies using neonatal rat ventricular myocytes with lamin A/C knockdown.
- In vivo gene therapy using adeno-associated virus (AAV)-mediated SIRT1 overexpression in Lmna-/- mice.
Main Results:
- Lmna-/- mice developed cardiac dysfunction and mitochondrial abnormalities by 1 month of age.
- Down-regulation of mitochondrial function and SIRT1 was observed in early-stage Lmna-/- hearts.
- SIRT1 overexpression improved mitochondrial respiration in vitro and alleviated cardiac dysfunction, fibrosis, and mortality in Lmna-/- mice in vivo.
- The study identified the SIRT1-PARKIN axis as a key mechanism linking LMNA to mitochondrial bioenergetics.
Conclusions:
- LMNA is crucial for maintaining mitochondrial bioenergetics via the SIRT1-PARKIN pathway.
- Targeting the SIRT1 signaling pathway represents a promising novel therapeutic strategy for DCM caused by LMNA mutations.
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