Is the exercise-regulated myokine-like small molecule beta-aminoisobutyric acid a paracrine signal and exercise mimetic?

Exercise is an important part of maintaining a healthy lifestyle across an individual's lifespan. Just how the body turns the efforts of exercise into improvements in health, however, is not fully understood. Exercise requires complex communication between different organs and tissues in the body: the protein PGC-1alpha coordinates some of the body's response to exercise, particularly in muscle. How PGC-1alpha "talks" to other tissues outside of muscle cells, though, was unknown.

Our previous research demonstrated that during exercise, PGC-1alpha causes muscle cells to release a messenger molecule called Beta-aminoisobutyric acid (BAIBA). We found that BAIBA modifies fat cells by making energy-storing white fat cells become more like calorie-burning brown fat cells. The BAIBA produced in muscle in response to exercise is released into the blood and boosts metabolism in other tissues.

Mice given BAIBA burned more calories, gained less weight and had better glucose metabolism than untreated mice. We also found that people with more BAIBA in their blood had lower indicators of health risk such as high cholesterol levels and high blood glucose.

In our recent research, we, and other researchers, have seen that BAIBA may also communicate messages back to muscle. In this proposed investigation, we ask whether BAIBA may therefore contribute to the way muscles adapt to exercise to produce improvements in exercise capability and performance. We also aim to determine if BAIBA can mimic some of the effects of exercise in muscle.

Specifically, this study will investigate how BAIBA affects genes and proteins regulating, and associated with, aspects of exercise adaptation, including fuel metabolism, protein metabolism, muscle structure and stimulation of blood vessel growth in human muscle cells. We will examine whether giving BAIBA to mice improves the ability of their muscles to perform work, use fuel (fat and carbohydrates) and to resist tiring.

We will also investigate whether BAIBA causes muscle from the mice to activate genes associated with exercise to increase the numbers of their mitochondria (the "powerhouses" of the cells), turn fuel into energy, change the structure of the muscle to resemble the effects of exercise training and increase muscle blood supply. Finally, we will investigate whether the exercise mimicking effects of BAIBA on muscle result in improved exercise performance, efficiency and muscle metabolism.

Ultimately, this study has the capacity to identify whether BAIBA can mimic the effects of exercise in muscle to improve muscle performance. This is potentially important in situations where exercise/physical performance is impaired or needs to be improved, such as in individuals affected by debilitating muscle wasting diseases, or in sports nutrition.

The ability to stimulate aspects of exercise in muscle using BAIBA may also be important for people incapable of exercise training through disability or illness.