Key result
Cardiomyocyte-specific deletion of SCOT in mice caused progressive cardiac dysfunction and remodeling during aging, which was partially mitigated by a ketogenic diet.
Why the study?
Although ketolysis is dispensable for cardiac development and function in mice, the long-term consequences of ketolysis downregulation in the heart remain unknown.
Does ketone catabolism and/or ketogenic diet prevent age-related cardiac dysfunction in mice?
Does ketone catabolism and/or ketogenic diet prevent age-related cardiac dysfunction in mice?
Ketone catabolism is essential for maintaining normal heart function during aging, and exogenous ketones confer cardioprotection independently of ketone oxidation.
Should not yet change practice; leaves open ketone signaling as a target for age-related cardiac decline.
The heart utilizes various nutrient sources for energy production, primarily favoring fatty acid oxidation. While ketones can be fuel substrates, ketolysis has been shown to be dispensable for heart development and function in mice. However, the long-term consequences of ketolysis downregulation in the heart remain unknown. Here we demonstrate that ketone catabolism is essential for preserving cardiac function during aging. The cardiac expression of succinyl-CoA:3-ketoacid CoA transferase (SCOT), a rate-limiting enzyme in ketolysis, decreases with aging in female mice. SCOT cardiomyocyte-specific knockout (cKO) mice exhibit normal heart function at 10 weeks of age but progressively develop cardiac dysfunction and remodeling as they age, without overt hypertrophy in both sexes. Notably, ketone supplementation via a ketogenic diet partially rescues contractile dysfunction in SCOT cKO mice, suggesting ketone oxidation-independent mechanisms contribute to the development of cardiomyopathy caused by SCOT downregulation. These findings indicate that ketone catabolism is crucial for maintaining heart function during aging, and that ketones confer cardioprotection independently of ketone oxidation.
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Keller et al. (2025) studied Cardiac aging and heart failure. Cardiomyocyte-specific knockout of SCOT (cKO) vs. Control mice (f/f and αMHC-Cre alone) was evaluated on Cardiac contractile function and remodeling. Cardiomyocyte-specific deletion of SCOT in mice caused progressive cardiac dysfunction and remodeling during aging, which was partially mitigated by a ketogenic diet.
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