Ketone flux through BDH1 supports metabolic remodeling of skeletal and cardiac muscles in response to intermittent time-restricted feeding

• Published in: Cell metabolism 2024-02, Vol.36 (2), p.422-437.e8
• Main Authors: Williams, Ashley S., Crown, Scott B., Lyons, Scott P., Koves, Timothy R., Wilson, Rebecca J., Johnson, Jordan M., Slentz, Dorothy H., Kelly, Daniel P., Grimsrud, Paul A., Zhang, Guo-Fang, Muoio, Deborah M.
• Format: Article
• Language: English
• Subjects: acylcarnitines; Animals; beta-oxidation; fiber type; Heart; intermittent fasting; ketones; Ketones - metabolism; metabolic flux; Mice; mitochondria; Mitochondria - metabolism; Muscle, Skeletal - metabolism; Myocardium - metabolism; Oxidation-Reduction; proteomics; striated muscles; time-restricted feeding
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2024.01.007

Time-restricted feeding (TRF) has gained attention as a dietary regimen that promotes metabolic health. This study questioned if the health benefits of an intermittent TRF (iTRF) schedule require ketone flux specifically in skeletal and cardiac muscles. Notably, we found that the ketolytic enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1) is uniquely enriched in isolated mitochondria derived from heart and red/oxidative skeletal muscles, which also have high capacity for fatty acid oxidation (FAO). Using mice with BDH1 deficiency in striated muscles, we discover that this enzyme optimizes FAO efficiency and exercise tolerance during acute fasting. Additionally, iTRF leads to robust molecular remodeling of muscle tissues, and muscle BDH1 flux does indeed play an essential role in conferring the full adaptive benefits of this regimen, including increased lean mass, mitochondrial hormesis, and metabolic rerouting of pyruvate. In sum, ketone flux enhances mitochondrial bioenergetics and supports iTRF-induced remodeling of skeletal muscle and heart. [Display omitted] •iTRF-induced muscle remodeling coincides with systemic adaptations in ketone flux•Muscle ketone flux depends on fiber-type-specific mitochondrial BDH1 abundance•BDH1 flux in striated muscles fine-tunes fat oxidation and pyruvate partitioning•BDH1 flux in striated muscles optimizes the metabolic benefits of iTRF Researchers found that ketone flux in cardiac and skeletal muscles promotes exercise tolerance and contributes to the full adaptive benefits of an intermittent time-restricted feeding (iTRF) regimen, both attributable to an unexpected interplay between ketolysis and fat burning efficiency that occurs selectively in mitochondria residing within highly oxidative myofibers.