MondoA deficiency enhances sprint performance in mice

Area of Science:

• Metabolic regulation
• Skeletal muscle physiology
• Transcription factors

Background:

• MondoA (basic helix-loop-helix/leucine zipper transcription factor) is primarily in skeletal muscle.
• MondoA:Mlx heterodimer senses cellular energy and targets genes like Txnip and glycolytic enzymes.
• In vitro studies suggest MondoA's role in energy metabolism.

Purpose of the Study:

• To investigate the in vivo function of MondoA in skeletal muscle metabolism and fuel selection.
• To characterize the metabolic phenotype of MondoA-inactivated mice.

Main Methods:

• Gene targeting to generate MondoA-inactivated (MondoA-/-) mice.
• Analysis of serum metabolites (lactate, alanine) and fuel utilization during exercise.
• Gene expression and promoter analysis to identify MondoA-regulated pathways.
• Dynamic exercise testing to assess performance and muscle glycolytic capacity.

Main Results:

• MondoA-/- mice displayed normal growth but unique metabolic characteristics.
• Elevated serum lactate and alanine levels were observed in MondoA-/- mice.
• MondoA-/- mice utilized fatty acids during exercise and showed enhanced glycolytic capacity.
• MondoA was found to repress PGC-1α-mediated PDK4 transcription, diverting pyruvate to lactate/alanine.

Conclusions:

• MondoA plays a crucial role in regulating fuel selection in skeletal muscle.
• Lack of MondoA leads to increased reliance on glycolysis and enhanced sprinting ability.
• This study uncovers a novel function of MondoA in vivo metabolic control.