The alternative splicing generated muscle-specific MEF2Dα2 isoform promotes muscle ketolysis and running capacity in mice

ABSTRACT Ketone bodies are an alternate fuel source generated by the liver in response to low carbohydrate availability in neonates and after starvation and exhausting exercise in adulthood. The postnatal alternative splicing generates a highly conserved muscle-specific MEF2Dα2 protein isoform of the transcription factor MEF2D. Here, we discovered that compared to WT mice, MEF2Dα2 exon knockout (Eko) mice displayed reduced running capacity and muscle expression of all three ketolytic genes, BDH1, OXCT1, and ACAT1. Consistent with reduced muscle utilization of ketone bodies, MEF2Dα2 Eko mice also showed increased ketone body levels in a tolerance test, after exercise, and upon feeding a ketogenic diet. Lastly, using mitochondria isolated from skeletal muscle, we showed reduced ketone body utilization and respiration in Eko compared to WT mice. Thus, we identified a new role of MEF2Dα2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity, and its effect on systemic ketone body levels.