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.
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November 2014
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Research Article|
October 23 2014
MondoA deficiency enhances sprint performance in mice
Minako Imamura;
Minako Imamura
1
*Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
†Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
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Benny Hung-Junn Chang;
Benny Hung-Junn Chang
*Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
†Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
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Motoyuki Kohjima;
Motoyuki Kohjima
*Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
†Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
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Ming Li;
Ming Li
*Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
†Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
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Byounghoon Hwang;
Byounghoon Hwang
‡Richard Roudebush VA Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
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Heinrich Taegtmeyer;
Heinrich Taegtmeyer
§Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
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Robert A. Harris;
Robert A. Harris
‡Richard Roudebush VA Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
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Lawrence Chan
Lawrence Chan
2
*Department of Molecular & Cellular Biology, Baylor College of Medicine, Houston, TX 77030, U.S.A.
†Diabetes Research Center, Baylor College of Medicine, Houston, TX 77030, U.S.A.
∥Department of Medicine, Baylor College of Medicine, Houston, TX 77030, U.S.A.
¶Baylor St. Luke's Medical Center, Houston, TX 77030, U.S.A.
2To whom correspondence should be addressed (email lchan@bcm.edu).
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Biochem J (2014) 464 (1): 35–48.
Article history
Received:
April 24 2014
Revision Received:
August 19 2014
Accepted:
August 22 2014
Accepted Manuscript online:
August 22 2014
Citation
Minako Imamura, Benny Hung-Junn Chang, Motoyuki Kohjima, Ming Li, Byounghoon Hwang, Heinrich Taegtmeyer, Robert A. Harris, Lawrence Chan; MondoA deficiency enhances sprint performance in mice. Biochem J 15 November 2014; 464 (1): 35–48. doi: https://doi.org/10.1042/BJ20140530
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