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
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.