More on L-BAIBA as a Regulator of Improved Muscle Function in Response to Exercise
You might recall the paper published late last year, in which researchers reported that dietary supplementation with the L-form enantiomer of β-aminoisobutyric acid (L-BAIBA) enhanced the response of muscle and bone tissue to exercise in aged mice. L-BAIBA is one of many molecules both secreted by muscle cells during exercise, and which interact with muscle cells to produce benefits following exercise. Muscle tissue is metabolically active, and changes in muscle cell activity during exercise produce downstream effects on tissues throughout the body via signaling of this sort. That list of responsive tissues includes the muscle itself.
Last year's paper didn't discuss mechanisms, but fortunately the more recent open access publication noted here delves into the biochemistry that enables the level of L-BAIBA to determine the degree to which exercise produces benefits in muscle growth and function. L-BAIBA is an intermediary linking the activity of proteins that are more familiar to the research community in the context of muscle and aging, and indeed aging more broadly. It links the activity of PGC-1α, well investigated for its role in muscle tissue and exercise, to the effects of PPARα and PPARδ in various tissues important to energy metabolism. When there is too little L-BAIBA, the chain of cause and effect falters and the response to exercise is muted. But metabolism doesn't normally operate at peak efficiency, and it turns out that adding more L-BAIBA can improve the response to exercise.
The repeated contraction, coordination, and transfer of force by skeletal muscle is central to physical activity. Skeletal muscle acts as both a source and target of the systemic signals which contribute to the adaptive remodelling and beneficial effects of exercise. The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) controls the expression of metabolic genes within skeletal muscle and is a key regulator of the skeletal muscle adaptive response to exercise. Mice with muscle-specific PGC-1α expression exhibit enhanced endurance exercise performance. Exercise training enhances expression of PGC-1α in skeletal muscle, which stimulates mitochondrial biogenesis, fatty acid β-oxidation, glucose transport, as well as an induction of muscular fiber-type remodelling from glycolytic fast-twitch type IIX muscle fibers to intermediate type IIA and oxidative type I slow-twitch muscle fibers. These adaptations in muscle physiology contribute to improved aerobic and endurance exercise performance.
The production and secretion of exercise-responsive myokines, muscle-derived endocrine signals, contributes to interorgan coordination and the systemic adaptation to exercise. We demonstrated that exercise training-induced PGC-1α expression in skeletal muscle drives the biosynthesis and secretion of the non-protein β-amino acid, β-aminoisobutyric acid (BAIBA). BAIBA functions as an exercise and PGC-1α regulated myokine-like metabokine, which induces hepatic β-oxidation and subcutaneous adipose tissue browning through PPARα, with subsequent protective effects against markers of cardiometabolic disease. BAIBA is also a bone-protective factor that prevents osteocyte cell death and reduces insulin resistance and inflammation. However, the contribution of BAIBA to exercise-mediated skeletal muscle adaptation and exercise performance is not understood.
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.