Kumar Sushil, Ji Xuan, Iqbal Hina, Guan Xiangnan, Mis Brittany, Dave Devanshi, Kumar Suresh, Besler Jacob, Dash Ranjan, Xia Zheng, Singh Ravi K
Division of Pediatric Pathology, Department of Pathology, Milwaukee, WI, 55226, USA.
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, 53226, USA.
EMBO Rep. 2025 Sep 16. doi: 10.1038/s44319-025-00578-3.
During prolonged starvation and exhaustive exercise, when there is low availability of carbohydrates, the liver breaks down fatty acids to generate ketone bodies, which are utilized by peripheral tissues as an alternative fuel source. The transcription factor MEF2D undergoes regulated alternative splicing in the postnatal period to produce a highly conserved, muscle specific MEF2Dα2 protein isoform. Here, we discover that compared to WT mice, MEF2Dα2 exon knockout (Eko) mice display reduced running capacity and muscle expression of all three ketolytic enzymes: BDH1, OXCT1, and ACAT1. MEF2Dα2 Eko mice consistently show increased blood ketone body levels in a tolerance test, after exercise, and when fed a ketogenic diet. Lastly, using mitochondria isolated from skeletal muscle, Eko mice show reduced ketone body utilization compared to WT mice. Collectively, our findings identify a new role for the MEF2Dα2 protein isoform in regulating skeletal muscle ketone body oxidation, exercise capacity, and systemic ketone body levels.
在长期饥饿和力竭运动期间，当碳水化合物供应不足时，肝脏会分解脂肪酸以生成酮体，外周组织会将酮体作为替代燃料来源加以利用。转录因子MEF2D在出生后经历受调控的可变剪接，以产生一种高度保守的、肌肉特异性的MEF2Dα2蛋白异构体。在此，我们发现，与野生型小鼠相比，MEF2Dα2外显子敲除（Eko）小鼠的跑步能力以及三种酮解酶（BDH1、OXCT1和ACAT1）的肌肉表达均降低。在耐受性试验、运动后以及喂食生酮饮食时，MEF2Dα2 Eko小鼠的血液酮体水平持续升高。最后，利用从骨骼肌分离出的线粒体，与野生型小鼠相比，Eko小鼠的酮体利用率降低。总体而言，我们的研究结果确定了MEF2Dα2蛋白异构体在调节骨骼肌酮体氧化、运动能力和全身酮体水平方面的新作用。
