Imamura Minako, Chang Benny Hung-Junn, Kohjima Motoyuki, Li Ming, Hwang Byounghoon, Taegtmeyer Heinrich, Harris Robert A, Chan Lawrence
‡Richard Roudebush VA Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
§Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
Biochem J. 2014 Nov 15;464(1):35-48. doi: 10.1042/BJ20140530.
MondoA is a basic helix-loop-helix (bHLH)/leucine zipper (ZIP) transcription factor that is expressed predominantly in skeletal muscle. Studies in vitro suggest that the Max-like protein X (MondoA:Mlx) heterodimer senses the intracellular energy status and directly targets the promoter region of thioredoxin interacting protein (Txnip) and possibly glycolytic enzymes. We generated MondoA-inactivated (MondoA-/-) mice by gene targeting. MondoA-/- mice had normal body weight at birth, exhibited normal growth and appeared to be healthy. However, they exhibited unique metabolic characteristics. MondoA-/- mice built up serum lactate and alanine levels and utilized fatty acids for fuel during exercise. Gene expression and promoter analysis suggested that MondoA functionally represses peroxisome-proliferator-activated receptor γ co-activator-1α (PGC-1α)-mediated activation of pyruvate dehydrogenase kinase 4 (PDK-4) transcription. PDK4 normally down-regulates the activity of pyruvate dehydrogenase, an enzyme complex that catalyses the decarboxylation of pyruvate to acetyl-CoA for entry into the Krebs cycle; in the absence of MondoA, pyruvate is diverted towards lactate and alanine, both products of glycolysis. Dynamic testing revealed that MondoA-/- mice excel in sprinting as their skeletal muscles display an enhanced glycolytic capacity. Our studies uncover a hitherto unappreciated function of MondoA in fuel selection in vivo. Lack of MondoA results in enhanced exercise capacity with sprinting.
MondoA是一种主要在骨骼肌中表达的碱性螺旋-环-螺旋（bHLH）/亮氨酸拉链（ZIP）转录因子。体外研究表明，Max样蛋白X（MondoA:Mlx）异二聚体感知细胞内能量状态，并直接靶向硫氧还蛋白相互作用蛋白（Txnip）以及可能的糖酵解酶的启动子区域。我们通过基因靶向技术构建了MondoA失活（MondoA-/-）小鼠。MondoA-/-小鼠出生时体重正常，生长正常，看起来健康。然而，它们表现出独特的代谢特征。MondoA-/-小鼠在运动过程中血清乳酸和丙氨酸水平升高，并利用脂肪酸作为燃料。基因表达和启动子分析表明，MondoA在功能上抑制过氧化物酶体增殖物激活受体γ共激活因子-1α（PGC-1α）介导的丙酮酸脱氢酶激酶4（PDK-4）转录激活。PDK4通常下调丙酮酸脱氢酶的活性，丙酮酸脱氢酶是一种催化丙酮酸脱羧生成乙酰辅酶A以进入三羧酸循环的酶复合物；在缺乏MondoA的情况下，丙酮酸转向糖酵解产物乳酸和丙氨酸。动态测试显示，MondoA-/-小鼠在短跑方面表现出色，因为它们的骨骼肌显示出增强的糖酵解能力。我们的研究揭示了MondoA在体内燃料选择中迄今未被认识的功能。缺乏MondoA会导致短跑运动能力增强。
