Muscle and bone communicate through the production of myokines and osteokines (12). Contracted muscle and loaded bone produce beneficial signaling molecules while unloaded muscle and resorbing bone produces molecules that have negative effects on the opposing tissue. Myokines can have autocrine, paracrine, and endocrine functions (13). An example of a negative myokine is myostatin also known as growth and differentiation factor 8 (GFD-8), a ubiquitous glycoprotein that negatively regulates skeletal and cardiac muscle, and reduces bone mass by stimulating osteoclast activity (14) through the activin type IIB receptor (ActRIIB) (15). An example of a positive myokine is irisin, released by the cleavage of the extracellular domain of the transmembrane receptor fibronectin II domain-containing 5 (FNDC5) (16), and has been found to be associated with browning of white adipose tissue and with energy metabolism (13). Several other factors are produced by sedentary and contracted muscle not reviewed here. {For review see (12, 17)}.
Conversely, bone produces osteokines such as osteocalcin, encoded by the BGLAP gene with a unique G-protein coupled receptor -GPRC6A that has a significant role in energy metabolism (glucose and fatty acids), in adipose, muscle and neuronal tissue (12, 18). Osteocalcin together with IL-6 from skeletal muscle increase adaption during exercise by providing the necessary carbon atoms to the TCA cycle (19). PGE2 is an eicosinoid made by loaded osteocytes that stimulates proliferation of satellite cells (muscle stem cells) through upregulation of the peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1 α) expression (20). Osteocytes are a major source of PGE2 especially in response to mechanical loading and secrete 1,000–10,000 times the amount produced by muscle cells (12).
β-aminobutyric acid (BAIBA) is a small non-protein metabolite. In humans, BAIBA has a metabolic effect by reducing insulin resistance (2). Several studies in animal models and humans have measured total BAIBA, but not its enantiomers. We showed that murine contracted muscle produces the L but not the D-enantiomer and that L-BAIBA has a protective effect on bone (6). A recent study of heart failure in rats showed that L-BAIBA produced during treadmill exercise has a protective effect on cardiac muscle cells (21).
The synergistic action of bone and muscle during exercise allows standing and moving – physical performance - and leads to movement and energy consumption (22). Exercise represents the planned, structured and repetitive physical activity with the goal to improve physical fitness. It is divided in two types: aerobic or endurance and anaerobic or resistance (22). It is not known which form or combination is most conducive to the production of BAIBA and if any associations exist for bone and muscle health.
A study in Native American boys and girls (11–17 years) divided into obese and normal-weight groups, measured blood BAIBA levels after 16 weeks of aerobic exercise training and showed that the normal-weight group had 29% higher BAIBA levels than those in the obese group (23). Physical inactivity in patients on hemodialysis has been found to reduce plasma BAIBA concentrations (24, 25), and plasma BAIBA levels are higher in young subjects than the elderly (26). This could be because BAIBA expression is regulated by PGC-1α, and PGC-1α expression is lower in elderly subjects compared to young subjects (27, 28). Additionally, high plasma BAIBA concentrations were observed in humans undergoing aerobic exercise but are inversely correlated with metabolic risk factors, suggesting that BAIBA may protect against metabolic diseases (2, 29–31).
For this retrospective single center study, our hypothesis was that physical performance would increase the BAIBA enantiomers levels and therefore serve as a biomarker for high performance. The primary aim was to determine if a correlation existed between L- or D- BAIBA with different physical tests in both males and females from different ages (20–34, 35–49, 50–64, 65+) and different levels of physical performance (LP, AP and HP groups). A study by Roberts et al performed with 80 healthy participants, both genders, mean age of 34 years, previously sedentary, with a 20-week aerobic training, showed a total BAIBA increase of 17% (2). A 2016 study in 49 patients with chronic kidney disease on hemodialysis, showed that BAIBA (probably L-BAIBA, based on what was mentioned in the manuscript that the BAIBA is generated from valine) was lower in hemodialysis physically inactive patients compared to active patients (able to exercise at least once a week) (24). The first clinical study (pubmed search till June of 2022) where the enantiomers and not total BAIBA were quantitated was in 2019 and showed that L-BAIBA increased during aerobic exercise and continued to increase at 30 min after participants completed the exercise schedule. D-BAIBA also increased during exercise but dropped at 30 min after the exercise schedule (30). In 2017 a cyclic exercise study with 13 untrained male participants did not show an increase of total BAIBA during exercise, however, a small increase was noted at 4 hours (32) .
In the present study, for the 120 total participants, L-BAIBA positively correlated with BMI and total fat mass. But BMI is a rough estimate of relative body weight, not accurate for body composition and does not include fat mass (33). In the 60 male participants, L-BAIBA associated with total fat mass and in the 60 female participants, with BMI and subtotal and total BMD. With regards to physical performance, in the male high performing group, L-BAIBA was negatively linked with femoral neck BMD whereas in the female high performing group, L-BAIBA had a positive association with femoral neck BMD and lean mass. In the average male performers, L-BAIBA had a negative association with femoral neck BMD, while in females, L-BAIBA was positive with BMI and total % fat. L-BAIBA had a positive association with 6MWT in low performing males, but a negative with appendicular lean/height^2 (kg/m^2) in low performing females. It was surprising that L-BAIBA would be so strongly associated with parameters of fat mass. However, with high physical performance in females, this was reversed and became associated for BMD and lean mass. This suggests another function of L-BAIBA distinct from mediating the effects of exercise.
For the 120 total participants, D-BAIBA positively associated with age and gait speed. In the 60 male participants, D-BAIBA positively associated with femoral neck BMD and six-minute walk test (6MWT). With regards to physical performance, in the male high performing group, D-BAIBA had a negative correlation with appendicular lean/height^2 (kg/m^2). In the low performing males, D-BAIBA had a positive correlation with 6MWT. It is not clear why this enantiomer would be associated with age. Also, it is not clear why D-BAIBA would be positively associated with the 6MWT. Additional studies will be required.
Data analysis of the 120 de-identified human serum samples in this cohort, did not support the hypothesis of elevated L-BAIBA in high performing individuals. Although the chosen samples for analysis were from study participants without a chronic disease – not on prescription medications (for instance not on statins which are known to be associated with myopathy); there are limitations. The retrospective nature of the study from already collected blood samples, a single center study and the relatively small cohort of 120 samples may account for the lack of significance. A major limitation may be not knowing how soon after exercise the blood was drawn. It has recently been described that BAIBA secretion increases during and after exercise (34). Other confounding factors that could be considered include circadian rhythm, diurnal variation/time of the day in which blood samples were collected, the fact that the blood draws were either at the beginning or the end of the physical performance tests, exercise status is unknown, as is the use of vitamins and /or supplements. Hormone replacement or use of contraception was unknown in the samples collected from female participants. Diet was not controlled before participating in the study and dietary history was not collected. Also, the conversion of D-BAIBA to L-BAIBA and vice versa during exercise cannot be excluded. Clinical studies with measurement of BAIBA and its enantiomers during resistance exercise have not been performed to date. A future study where most of the above factors can be controlled, such as a study in healthy young untrained adults where the enantiomers and other ABAs and metabolites can be measured during and after the two different types of exercise (aerobic and resistance) could provide more information regarding the release, timing, and response to exercise.