The metabokine β-aminoisobutyric acid mediates exercise performance and skeletal muscle adaptation through a PGC1α-BAIBA-PPARδ axis
- Helene N. Daou
- Nicole T. Watt
- Shaimaa A. Gad
- Amanda DV MacCannell
- Aysha Ali
- Chew Cheng
- Raquel L. Fernando
- T. Simon Futers
- Sumeet A. Khetarpal
- Harrison Gallagher
- Luis D. Chinait
- Anselmo S. Moriscot
- Pim Knuiman
- Koen Manusama
- Marco Mensink
- Irvin Teh
- Jurgen E. Schneider
- Richard Cubbon
- Guy S. Taylor
- Daniel J. West
- David J. Beech
- T. Scott Bowen
- Lee D. Roberts
2026-08-18
Exercise orchestrates an interorgan communication network, in which skeletal muscle releases signaling molecules known as myokines that contribute to exercise training-induced adaptations. We identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a regulator of adipose and hepatic metabolic responses to exercise. Here, we demonstrate that BAIBA regulates muscle metabolism, morphology and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA’s biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.