Abstract Body: Background: Heart failure, characterized by a metabolic imbalance, leads to impaired mitochondrial ATP production. Ketone bodies not only serve as an alternate energy source but also mitigate heart failure by reducing cardiac remodeling and inflammation. The role of long noncoding RNAs (lncRNAs) in cardiac remodeling and mitochondrial metabolism is increasingly appreciated, and this study examines the effect of ketogenic diet on cardiac lncRNA regulation and mitochondrial protection.
Methods and Results: 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 (Keto; 80% fat, 15% protein, 5% carbohydrate). Data were analyzed using unpaired two-tailed t-tests (GraphPad Prism) and reported as mean ± SE. The keto diet significantly increased blood ketone bodies (n=36/group), indicating ketosis, and led to weight gain as well as a significant decrease in heart mass relative to body weight, suggesting cardiac metabolic adaptation (Fig 1A-B). The cardiac expression analysis of lncRNAs Anril, Caren, Carmn, Gm15441, Malat1, Miat, and Oip5-as1 via qPCR (n=13/group) revealed significant upregulation of Anril and Malat1 in the Keto hearts (Fig 1C-D), indicating their potential regulatory roles under ketogenic conditions. Sex-specific differences were not observed in the lncRNA expressions. Key proteins involved in mitochondrial biogenesis, protection, and metabolic adaptation, including Nrf2 and PGC1α, were significantly increased at both mRNA and protein levels (n=6-10) in the hearts of mice on keto diet (Fig 1E-H).
Conclusion: A six-month ketogenic diet in mice promotes cardiometabolic adaptations characterized by a reduction in relative heart mass and activation of key proteins involved in mitochondrial biogenesis and protection possibly through lncRNAs Anril and Malat1. These findings shed light on novel molecular targets and the potential of ketogenic diet/ketone bodies in treating heart failure.