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.

Background: Exercise is a systemic physiological process requiring co-ordination across multiple tissues and organs. Exercise training involves multiple bouts of activity that challenge whole-body physiology, driving adaptations across cells, tissues, and organs. Skeletal muscle integrates many of the systemic signals which regulate the adaptive response to exercise and contributes to the beneficial effects of exercise on cardiometabolic health. Elucidating the fundamental molecular mechanisms and intra- and inter-organ signals through which exercise mediates these systemic adaptations is a key challenge in understanding exercise physiology with implications for health and disease.
We previously discovered that the metabolite beta-aminoisobutyric acid (BAIBA) is secreted from muscle into the circulation during exercise. BAIBA increases hepatic beta-oxidation and induces browning of white adipose tissue to alter energy homeostasis, through a myokine-like mechanism, with anti-obesity/diabetic effects.
Aim: This study will determine whether BAIBA is also an autocrine/paracrine signal which functions as an exercise mimetic to induce exercise training-like effects in skeletal muscle and improve muscle function and exercise performance.
Approach: Using mouse and human primary myocytes and rodent models, we aim to determine whether BAIBA stimulates exercise-like effects in skeletal muscle including fibre-type switching, angiogenesis, oxidative mitochondrial metabolism and effects on protein homeostasis. Whether muscle BAIBA concentration is higher in a rodent model of inherited exercise capacity and whether BAIBA improves exercise efficiency and performance will be investigated.
Application: This study will determine if BAIBA has a fundamental role in mediating the adaptive effects of exercise in skeletal muscle. This may have therapeutic potential in a range of diseases of impaired muscle or metabolic function or in settings where the capacity to exercise is impaired.

This impact summary details how this BBSRC proposal will contribute to improvements in human health, and benefits to UK industry, competitiveness and wealth. This study will determine if the exercise-regulated metabolite myokine beta-aminoisobutyric acid (BAIBA) is also an autocrine/paracrine signal which functions as an exercise mimetic to induce exercise training-like effects in skeletal muscle and improve muscle function and exercise performance. Impact objectives include the protection of intellectual property (IP) and dissemination of the research findings to potential beneficiaries through both direct and indirect engagement. Immediately identifiable beneficiaries for this research include patient groups and the clinical scientific community (as a gateway to further impact), the sports nutrition and performance industry, pharmaceutical industry, nutrition and health supplement industry, health policy makers, and the public.
Patient Groups and Clinical Scientific Community: The potential to activate exercise-like effects in muscle offered by BAIBA may have therapeutic impact for patient groups affected by muscle wasting or dysfunction diseases and exercise intolerance (chronic obstructive pulmonary disease, diabetes, muscular dystrophy, chronic heart failure), potentially impacting millions of individuals in the UK (3.7 million people in the UK with diabetes). However to demonstrate effectiveness in these groups further research will be required with the engagement of the clinical scientific research community. The PI has identified potential collaborators within the clinical scientific community that are receptive to the future translation of the findings of this proposal to clinical studies in relevant patient groups.
Industry: The UK's pharmaceutical industry was estimated to have a turnover of over £32 billion in 2014. The pharmaceutical industry has been identified as a potential beneficiary of this research; especially if BAIBA is to show therapeutic potential in the treatment of diseases related to or involving skeletal muscle dysfunction and exercise intolerance.
Nutrition and Supplement Industry and Sports Nutrition and Performance: The U.K. nutritional supplement market is expected to reach $15 billion US by 2023. In 2015 UK consumers spent £66 million on sports nutrition alone. Key sector companies include Sanofi, GSK, Nestle Nutritionals, Pfizer and Bayer. BAIBA is a physiological water soluble amino acid, amenable to inclusion in dietary supplements or sports drinks/food. Evidence that BAIBA induces improvements in muscle function will have distinct applications in sports nutrition.
Public and Health Policy: This proposal may identify new therapeutic interventions for muscle wasting and dysfunction which could translate into new drugs and therapeutics, impacting the public over the long term. This research may also influence dietary / supplement policy. This will have a significant impact, not only on the quality of life of individuals affected by muscular diseases but could significantly reduce the economic burden of healthcare and influence policy makers in Public health England, UK Departments of Health, NICE and the NHS.
Scientific Training and Careers: This proposal will have a significant impact on the scientific staff funded by the award. The researchers will be trained in a diverse range of techniques, will develop their translational skills, and are expected to write publications in a scientific style and for a lay audience, conduct presentations at internal seminars and at scientific conferences, and supervise graduate and undergraduate students in the laboratory. The staff will have access to training courses at the University of Leeds. Therefore the employability of the researchers in scientific careers or beyond will be enhanced, and this study will contribute to training the next generation of scientists.