A 2-hydroxybutyrate-mediated feedback loop regulates muscular fatigue.

Area of Science:

• Biochemistry
• Metabolomics
• Skeletal Muscle Physiology

Background:

• Metabolites can exert biological functions beyond their canonical pathways.
• 2-Hydroxybutyrate (2HB) is a stress-induced metabolite that increases post-exercise and in metabolic disorders.
• The broader roles of metabolites like 2HB in cellular regulation are not fully understood.

Purpose of the Study:

• To investigate the molecular mechanisms by which 2-Hydroxybutyrate (2HB) influences skeletal muscle metabolism.
• To determine if 2HB can replicate exercise-induced improvements in metabolic function.

Main Methods:

• In vitro assays measuring enzyme inhibition and protein ADP-ribosylation.
• Cellular and animal models to assess transcriptional responses and oxidative capacity.
• Metabolite injection studies to compare effects with exercise training.

Main Results:

• 2-Hydroxybutyrate (2HB) inhibits branched-chain aminotransferase enzymes.
• This inhibition triggers a SIRT4-dependent decrease in nuclear protein ADP-ribosylation.
• 2HB induces a C/EBPβ-mediated transcriptional response, enhancing branched-chain amino acid degradation and improving oxidative capacity.
• Repeated 2HB administration mimics exercise-induced gains in oxidative capacity.

Conclusions:

• 2-Hydroxybutyrate (2HB) is a key regulator of skeletal muscle metabolism.
• 2HB acts through enzyme inhibition and modulation of protein modification to enhance cellular oxidative function.
• These findings reveal a novel link between a stress metabolite and exercise-mimetic effects on muscle.