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American Heart Association

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Final ID: Fri174

Long Noncoding RNA MALAT1-Mediated Cardiac and Mitochondrial Adaptations Under Ketotic Conditions in Mice and Human Cardiomyocytes

Abstract Body: Background: Heart failure is characterized by mitochondrial dysfunction and energy deficits. Ketone bodies help mitigate cardiac remodeling and inflammation, while long noncoding RNAs (lncRNAs) regulate cardiac remodeling and mitochondrial metabolism. This study investigates how ketotic conditions influence lncRNA regulation and mitochondrial protection in mouse hearts and human cardiomyocytes.
Methods and Results: To identify ketone body-regulated lncRNAs, we analyzed GEO dataset GSE206797, revealing six differentially expressed lncRNAs—Tug1, Carmn, Oip5, H19, Malat1, and Gm15441—in neonatal hearts lacking Hmgcs2, a key enzyme in ketone production. In a six-month study, 10-week-old male and female C57BL/6J mice were assigned to either a control diet (10% fat, 20% protein, 70% carbohydrate) or a ketogenic diet (80% fat, 15% protein, 5% carbohydrate). The ketogenic diet significantly increased blood ketone levels (n=36/group) and reduced heart mass relative to body weight. In ketogenic hearts, qPCR analysis (n=13/group) revealed significant upregulation of Malat1, which correlated with Pgc1α (R2=0.47; P=0.001) and Nrf2 (R2=0.34; P=0.01) expression. Mitochondrial biogenesis and protective proteins, including PGC1α and NRF2, were also significantly elevated in ketogenic hearts (n=6-10). In human AC16 cardiomyocytes, β-hydroxybutyrate (BHB) treatment (0.5, 1, and 5 mM for 24, 48, and 72 h) upregulated MALAT1 and key ketone oxidation genes (MCT1, BDH1, SCOT) (n=3). Additionally, BHB increased PGC1α, TFAM, and antioxidant genes (NRF2, SOD1, SOD2), while upregulating pyruvate dehydrogenase kinase, an inhibitor of glycolysis. Computational analysis (LncRRIsearch) identified strong RNA-RNA interactions between MALAT1 and PGC1α/NRF2. MALAT1 knockdown using 10 nM siRNA, combined with 5 mM BHB for 72 hours (n=3–6), significantly reduced cellular ATP levels, SCOT mRNA, NRF2 mRNA, and PGC1α protein in human cardiomyocytes (Fig. 1).
Conclusion: Ketosis induces mitochondrial adaptations by upregulating MALAT1 and mitochondrial protective genes, suggesting a regulatory axis involving MALAT1, PGC1α, and NRF2. These findings underscore the therapeutic potential of ketotic interventions in heart failure treatment.
  • Almalki, Bandar  ( Nova southeastern university , Davie , Florida , United States )
  • Gurusamy, Narasimman  ( NOVA SOUTHEASTERN UNIVERSITY , Fort Lauderdale , Florida , United States )
  • Murray, James  ( NOVA SOUTHEASTERN UNIVERSITY , Fort Lauderdale , Florida , United States )
  • Katragadda, Sai Chandra  ( Nova southeastern university , Davie , Florida , United States )
  • Tran, Talan  ( NOVA SOUTHEASTERN UNIVERSITY , Fort Lauderdale , Florida , United States )
  • Pulickathadam, Colin  ( NOVA SOUTHEASTERN UNIVERSITY , Fort Lauderdale , Florida , United States )
  • Faruqui, Sara  ( NOVA SOUTHEASTERN UNIVERSITY , Fort Lauderdale , Florida , United States )
  • Gill, Navdeep  ( Nova southeastern university , Davie , Florida , United States )
  • Speth, Robert  ( Nova Southeastern University , Davie , Florida , United States )
  • Robison, Lisa  ( Nova Southeastern University , Davie , Florida , United States )
  • Author Disclosures:
    Bandar Almalki: No Answer | Narasimman Gurusamy: DO NOT have relevant financial relationships | James Murray: No Answer | Sai Chandra Katragadda: No Answer | Talan Tran: No Answer | Colin Pulickathadam: DO NOT have relevant financial relationships | Sara Faruqui: DO NOT have relevant financial relationships | Navdeep Gill: No Answer | Robert Speth: DO NOT have relevant financial relationships | Lisa Robison: No Answer
Meeting Info:

Basic Cardiovascular Sciences 2025

2025

Baltimore, Maryland

Session Info:

Poster Session and Reception 3

Friday, 07/25/2025 , 04:30PM - 07:00PM

Poster Session and Reception

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