During physical exercise, muscles produce a small molecule that appears to help them build endurance, improve energy utilization, and adapt to repeated workouts. The study results were published in the journal Nature Communications.
Start running three times a week, and a month later, the same route will feel easier. Muscles undergo recovery to make this happen, and new research has shown that they cannot complete this process without a specific small molecule produced during exercise.
Muscles produce this molecule, called L-BAIBA, while working. Mice unable to produce it exercised at the same intensity but derived far fewer benefits from the activity. Virtually all this data comes from mice and human muscle cells grown in Petri dishes; human study participants provided only blood samples.
“Our research has shown that L-BAIBA is an exercise-activated signal that helps muscles adapt, improves their metabolic and contractile capabilities, and ultimately boosts physical performance,” said Professor Lee Roberts of the University of Leeds.
Muscles do more than just facilitate movement; they also act as a signaling organ, releasing chemical signals into the bloodstream. One such signal originates with valine, an amino acid found in protein-rich foods. A lack of dietary protein is linked to muscle weakness in older adults.
Muscles consume amino acids—the small building blocks of proteins—and valine is one of them. When valine is broken down inside a muscle cell, one of the resulting residues is a compound called beta-aminoisobutyric acid, or BAIBA for short.
In 2014, Roberts and his colleagues reported that physical exercise prompts muscles to produce more BAIBA, and that this extra BAIBA alters the way the body burns fat. It is now available as a supplement and is one of many compounds being investigated as a workout booster.
BAIBA exists in two mirror-image forms, and distinguishing between them was the first task of this study. Only one of these forms—L-BAIBA—had any effect on the muscles. This version is processed by a specific enzyme and functions within the muscle cell’s mitochondria—the compartments that convert food and oxygen into usable energy.
For six weeks, young male mice were given BAIBA in their drinking water at a dosage of 100 milligrams per kilogram of body weight daily. As a result, their blood levels of the substance reached concentrations comparable to those achieved through physical exercise.
The mice were then given access to a running wheel. Those treated with BAIBA ran faster and covered more revolutions, even though they didn’t approach the wheel more frequently than the others. Physical changes occurred in their legs: the soleus—a calf muscle associated with endurance—increased in weight and fiber count, including a rise in the number of slow-twitch, fatigue-resistant fibers.
When excised and stimulated in a bath, this muscle contracted more powerfully than that of a control animal. This was partly due to mitochondrial activity; the treated mice had more mitochondria in their muscles, allowing the tissue to utilize oxygen more efficiently. Weeks of endurance training alone yield roughly the same result by acting on muscles through their standard energy-sensing mechanism.
Adding the molecule was one test; a more complex one involved the reverse: removing it and then training the animal anyway. Roberts’s team injected short DNA strands into the hind-limb muscles of mice twice a week to suppress the enzyme responsible for the final step of L-BAIBA synthesis in that tissue.
Then, groups of ten mice trained on an inclined treadmill for six weeks—four days a week for 45 minutes. Typically, trained mice accumulate higher levels of L-BAIBA in their blood; however, these specific mice showed almost no such increase.
They gave up prematurely as they reached their limits and hit peak speed, and their calf muscles generated less force than would be expected from trained animals. The training regimens were identical; the only difference was that the muscles could not withstand the workload.
Sixty volunteers aged 18 to 65 underwent a treadmill test at Newcastle University to measure their maximum oxygen consumption—a standard indicator of aerobic fitness. During a subsequent visit, they walked on an incline for 45 minutes at 60% of their maximum intensity, with blood samples taken beforehand.
…of the exercise bout and at the moment of its completion.
Resting L-BAIBA levels correlated with physical fitness. The association was weak but statistically significant. The mirror-image form showed no link to fitness levels, whereas both forms increased immediately after exercise in both men and women. Another 33 people engaged in stationary cycling at Wageningen University for 10 weeks.
By the end of the experiment, their L-BAIBA levels were higher, but the levels of the mirror-image form were not. In this group, resting L-BAIBA levels corresponded to fitness levels about twice as accurately as in the first group.
None of this proves that the molecule improved a person’s physical fitness. The results obtained in humans support the findings from mouse studies, but they do not prove a causal link.
Mice fed a high-fat diet for eight weeks gained weight and struggled to clear sugar from their blood. They also ran less. Then, half of them were given BAIBA for another 14 weeks, while the others remained on the diet alone.
The treated group regained the distance covered in a 24-hour period. Their soleus muscles recovered mass and fiber count, and maintained strength longer before fatigue set in. A mouse on a high-calorie diet is not a human with type 2 diabetes, and this distinction matters.
“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,” said Anna Morris, Assistant Director of Research Strategy and Partnerships at Diabetes UK. “Although these results are still in the early stages, they could help shape future approaches that enable people with type 2 diabetes to stay active and live longer, healthier lives.”
No humans took L-BAIBA in the study. The human aspect of the work involved analyzing blood biochemistry—specifically, who took the drug, in what amounts, and when. Age also influenced the outcome. Young mice treated with BAIBA showed growth of additional muscle fibers. Mice treated later in adulthood did not experience this; instead, they restored existing fibers.
Older adults frequently lose strength and speed—a loss that can be measured using simple muscle power tests. The experiments did not use truly aged animals. In the first experiment, all the mice were male, and all exercise regimens were aerobic. The question of whether weightlifting sends the same signal remains open.
“This gives us exciting new insight into how exercise benefits the body and points to a promising target for future therapies aimed at preserving muscle function in chronic diseases like diabetes,” says Roberts.
The next step is testing L-BAIBA in humans. Roberts and his colleagues plan to start with patients who have type 2 diabetes and then expand the research to conditions that cause muscle atrophy, such as heart failure and cancer.
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