An international research team headed by scientists at the University of Leeds discovered that a key molecule released during exercise strengthens muscles, improves exercise performance, and could be a therapeutic treatment for muscle damage caused by type 2 diabetes. Their collective results of the study, involving experiments in mice, and human plasma analyses, identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a central regulator of how muscles remodel, strengthen, and improve their endurance in response to exercise training. The findings further showed that it’s the L-enantiomer, L-BAIBA, that acts as the primary mediator of muscular effects.

Research lead Lee Roberts, PhD, professor of molecular physiology and metabolism at the University of Leeds, said, “Our research identifies L-BAIBA as an exercise-induced signal that helps muscles adapt, improve their metabolic capacity and ability to contract, and ultimately enhances physical performance. This gives us exciting new insight into how exercise benefits the body and highlights a promising target for future therapies aimed at preserving muscle function in chronic conditions such as diabetes.”

Roberts is senior and corresponding author of the team’s published paper in Nature Communications, titled “The metabokine β-aminoisobutyric acid mediates exercise performance and skeletal muscle adaptation through a PGC1α-BAIBA-PPARδ axis.” In their paper, the team noted, “It may be that BAIBA can offer a novel therapy for other diseases with a skeletal muscle atrophy or dysfunction component, such as chronic heart failure, cancer cachexia, or sarcopenia. Conducting intervention studies using BAIBA to target muscle function, exercise capacity, and quality of life in these clinical populations will be important for future translation.”

Exercise training involves multiple bouts of activity that challenge whole-body physiology, driving adaptations across cells, tissues, and organs, the author wrote. “Exercise is also an effective intervention for the prevention or treatment of a range of diseases and pathological risk factors, including obesity, type 2 diabetes (T2D), and cardiovascular disease, and may facilitate improvements in age-related reduction in quality of life.”

But how exercise impacts the body’s ability to respond to challenges is not fully understood. The team continued, “Elucidating the fundamental molecular mechanisms and intra- and inter-organ signals through which exercise mediates systemic adaptations, driving beneficial effects, holds potential for the identification of both therapeutic targets and new strategies to treat a range of diseases, including T2D.”

Given the health benefits of exercise, Roberts and colleagues set out to discover whether this mechanism could hold the potential for treatment for chronic conditions such as type 2 diabetes. L-BAIBA has been studied in the past, and Roberts carried out research in 2014, which showed that it had beneficial effects on metabolism, boosting the fat-burning effects of exercise. It can now be purchased as a nutritional supplement.

The newly reported study has found that it triggers muscles to respond and change, linking exercise to beneficial alterations in muscle structure and metabolism. “Circulating L-BAIBA associated with aerobic fitness in humans,” the team noted in summary. “The current study identified that in mice, BAIBA supplementation in drinking water increases skeletal muscle mitochondrial number and functional capacity, improves muscle contractile function, and drives phenotypic remodelling similar to aerobic exercise training. We find that BAIBA supplementation in mice, when combined with exercise training through wheel running, leads to an increased adaptive response in skeletal muscle.”

L-BAIBA also protected muscle from damage that occurs in type 2 diabetes, which can limit a person’s quality of life, such as loss of muscle and strength, and impaired metabolism. Improving muscle resistance to fatigue could be transformative, as exercise can help to manage diabetes. The discovery that BAIBA not only mimics the adaptive response of muscle to exercise but can also contribute to translating the benefits of exercise to improved muscle and systemic function may have important clinical implications, the investigators continued. “In our study, BAIBA treatment exhibited therapeutic potential by improving the free-wheel running capacity and skeletal muscle molecular, metabolic, and functional phenotype in a mouse model of obesity and T2D-induced skeletal muscle dysfunction.”

Anna Morris, assistant director of research strategy and partnership at Diabetes UK, said, “Exercise plays an important role in managing type 2 diabetes, but for many people, muscle weakness and fatigue can make staying active a real challenge. This research helps us better understand how muscles adapt to exercise and identifies a potential new target for improving muscle health. While these findings are still at an early stage, they could help shape future approaches that support people with type 2 diabetes to remain active and live healthier, longer lives.”

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