MondoA deficiency enhances sprint performance in mice

Minako Imamura, Benny Hung Junn Chang, Motoyuki Kohjima, Ming Li, Byounghoon Hwang, Heinrich Taegtmeyer, Robert A. Harris, Lawrence Chan

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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 peroxisomeproliferatoractivated 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.

Original languageEnglish
Pages (from-to)35-48
Number of pages14
JournalBiochemical Journal
Volume464
DOIs
Publication statusPublished - Nov 15 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Imamura, M., Chang, B. H. J., Kohjima, M., Li, M., Hwang, B., Taegtmeyer, H., Harris, R. A., & Chan, L. (2014). MondoA deficiency enhances sprint performance in mice. Biochemical Journal, 464, 35-48. https://doi.org/10.1042/BJ20140530