Scientists at the University of Houston have revealed a promising new approach to managing diabetic ketoacidosis (DKA), a dangerous complication affecting about 20-30% of diabetic patients globally. Their research, led by Assistant Professor Ravi K. Singh and published in EMBO Reports, focuses on the muscle-specific protein isoform MEF2Dα2, which plays a key role in regulating skeletal muscle metabolism of ketone bodies and exercise capacity.
DKA arises when ketone levels in the blood become excessively high, leading to toxicity. While ketones serve as an alternative energy source during low-carbohydrate intake-such as in ketogenic diets, excessive accumulation can be life-threatening, particularly in diabetic patients. Singh’s team discovered that MEF2Dα2 influences how effectively skeletal muscles oxidize ketones, impacting both systemic ketone levels and exercise endurance.
Using advanced CRISPR/Cas9 gene editing, the researchers specifically disabled the MEF2Dα2 isoform in muscle tissue. They then measured the expression of enzymes involved in ketone metabolism and assessed physical exercise capacity in experimental models. Subjects lacking MEF2Dα2 exhibited reduced expression of ketone-metabolizing enzymes and impaired ability to utilize ketones during physical activity. Additionally, the team monitored ketone levels after consuming high-fat ketogenic diets and after exercise to evaluate metabolic effects.
Knockout of MEF2Dα2 led to reduced ketone utilization in muscles, causing elevated blood ketone concentrations post-exercise and after a ketogenic diet. These results establish that MEF2Dα2 is critical for maintaining optimal ketone oxidation in skeletal muscle, thus regulating systemic ketone balance and supporting exercise capacity. Singh suggests that targeting MEF2Dα2 function may enhance exercise tolerance and help manage dangerously high ketone levels in diabetic patients, potentially reducing DKA risk and improving clinical outcomes.
This innovative study opens avenues for therapies that optimize muscle ketone metabolism, offering new hope to millions at risk of ketoacidosis worldwide.
REFERENCE: Kumar, S., et al. (2025). The muscle specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice. EMBO Reports. doi.org/10.1038/s44319-025-00578-3
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