title: MondoA deficiency enhances sprint performance in mice.
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 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.
authors.forename: Minako
authors.initials: M
authors.lastname: Imamura
authors.forename: Benny Hung-Junn
authors.initials: BH
authors.lastname: Chang
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Kohjima
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: ‡Richard Roudebush VA Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
authors.forename: Byounghoon
authors.initials: B
authors.lastname: Hwang
authors.affiliation: §Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, U.S.A.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.affiliation: ‡Richard Roudebush VA Medical Center, 1481 West Tenth Street, Indianapolis, IN 46202, U.S.A.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000172:deficiency*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism*; D009924:Organ Culture Techniques; D010805:Physical Conditioning, Animal / Q000379:methods / Q000502:physiology*; D010807:Physical Endurance / Q000502:physiology*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C550079:MondoA protein, mouse