Metabolic Syndrome, Musculoskeletal, Neurology

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

Intermittent fasting (IF) and time-restricted feeding (TRF) are dietary regimens known to produce favorable metabolic outcomes. During periods of fasting, ketones are well-recognized as an essential fuel for the brain, while their role in skeletal muscle and heart has been explored less.

This study investigated muscle ketone metabolism in mice during a newly developed intermittent TRF (iTRF) schedule, consisting of 4 days of 18-hour fasting (to drive a strong ketogenic response) followed by 3 days of unrestricted feeding (to allow recovery).

Mitochondria in heart and skeletal muscles are highly efficient at fatty acid oxidation (FAO) and contain high amounts of the enzyme beta-hydroxybutyrate dehydrogenase 1 (BDH1). This study used mice with a deficiency of BDH1 in their striated muscles to understand the enzyme’s role.

Key findings:

• Muscle remodeling and ketone flux: The benefits of iTRF on muscle remodeling were closely linked to ketone flux via BDH1, particularly in the heart and oxidative skeletal muscle.
• Fat oxidation and exercise tolerance: Mice deficient in BDH1 showed impaired fat oxidation and reduced exercise tolerance during fasting, indicating that BDH1 is critical for efficient mitochondrial function in muscle.
• Metabolic benefits of iTRF: iTRF led to significant muscle remodeling, such as increased lean mass and enhanced mitochondrial bioenergetics, but these benefits were diminished in BDH1-deficient mice.

Conclusions

These findings provide new insights into the importance of ketones in skeletal and cardiac muscle metabolism. Understanding these mechanisms deepens our knowledge of how fasting promotes muscle remodeling, enhances mitochondrial efficiency, and optimizes energy utilization. These insights have potential applications in developing therapeutic strategies to improve metabolic health and muscle function.