Organisms maintain their life activities through the transformation of substances into energy; small-molecule products in this process are called metabolites (1). Some metabolites that participate in the transmission of information between cells are referred to as signaling metabolites (2). They represent important control points in homeostasis and may serve as biomarkers of diseases. Previous studies had suggested β-aminoisobutyric acid (BAIBA) as a muscle factor (myokine); however, BAIBA, being an amino acid metabolite, is neither a protein nor an active peptide, and may be more appropriately referred to as a muscle signaling metabolite.

BAIBA is a catabolic metabolite of thymine and valine in skeletal muscle (3). It is present as D- and L-enantiomers in mammals, D-BAIBA being an intermediate product of thymine degradation in the cytoplasm, and L-BAIBA being produced by L-valine decomposition (3). In 2014, Roberts et al. (4) had observed a significant increase in BAIBA synthesis in myoblasts, after PGC-1α treatment, by liquid chromatography-liquid mass spectrometry (LC-MS). Subsequent in-vivo and ex-vivo experiments confirmed that BAIBA might promote the differentiation of pre-adipocytes into brown fat, promoting free fatty acid (FFA) oxidation (4, 5) Further, BAIBA was considered to indirectly up-regulate browning and fatty acid oxidation in the liver, maintain lipid homeostasis, and prevent and improve lipid metabolism disorders (4, 6–15). In addition, BAIBA was reported to improve glucose homeostasis in mice (8, 13, 16); it could regulate the differentiation of osteoprogenitor cells, affect the balance between the number of osteoblasts and osteoclasts, maintain bone mass homeostasis (17, 18), reduce inflammatory response and oxidative stress (17, 19), and improve related diseases (4, 8, 14, 15, 20). Overall, BAIBA has drawn abundant attention of researchers recently.

The synthesis and metabolism of BAIBA are closely related to exercise, and no adverse effect has been observed in subjects, animals, or cells receiving different doses of BAIBA, suggesting its potential to be developed as an exercise pill. In addition, BAIBA has been associated with the development of osteoporosis and neo-coronary pneumonia; however, differences in conditions used by different investigators may be fundamental to BAIBA’s role as a disease marker. The only review on BAIBA till date has reported its relationship with lipid metabolism (21), and the mechanisms of action of BAIBA are still mostly speculative. Therefore, in this review, we discussed the biological functions of BAIBA, its relationship with exercise, drug applicability, and considerations of it being a disease marker, in order to provide a theoretical basis for the study of BAIBA and related diseases.

Thymine and dihydro pyrimidine dehydrogenase ((DPYD)) and hydrogen reacted to form two Thymine (Dihydrothymine) (22). Dihydrothymine combined with dihydropyrimidinase (DPYS) to form N-carbamoyl-β-amino-isobutyric acid (N-carbamoyl-BAIBA). After further reaction of D-BAIBA by N-carbamoyl-BAIBA and beta-ureidopropionase (UPB1), D-methylmalonic semialdehyde (D-MMS) was finally produced through AGXT2 in mitochondria (23). Studies have detected the expression level of AGXT in various organs such as the brain, liver, pancreas, spleen, heart, lung, esophagus, stomach, small intestine, colon, skeletal muscle, kidney, thymus, testis, ovary, uterus, prostate, tongue and skin. It was found that the expression level was higher in the liver and kidney.

L-BAIBA was produced by catabolism of the branched amino acid L-VALINE (24). L-VALINE was formed under ammonia, and the oxidation reaction of methyl malonyl half aldehyde (L-methylmalonylsemialdehyde, L-MMS). L-MMS produced L-BAIBA in reaction with mitochondrial enzyme 4-aminobutyrate aminotransferase (ABAT) (25, 26). It has been reported that the production of L-BAIBA by ABAT is a bidirectional reaction, so the same enzyme can catalyze the conversion of L-BAIBA to L-MMS. At the same time, the Malonate – semialdehyde dehydrogenase (MMSDH), can L-oxide MMS and D-MMS propionyl coa (24). L-BAIBA is converted to D-BAIBA and vice versa through the stereoisomerization pathway between L-MMS and D-MMS (24, 27). MMSDH has been less reported in organs and seems to be concentrated in the liver.

BAIBA acts as a signaling metabolite and an antioxidant that is regulated by exercise, as validated at multiple levels (animal, cellular, protein, and genetic) (73–75).

Serum BAIBA levels are not significantly altered in adult male participants either immediately after acute aerobic exercise (70% of maximal oxygen uptake), or after 1 h, or even 4 h (75). Interestingly, serum D-BAIBA and L-BAIBA levels increased by 13% and 20%, respectively, after 1 h of acute aerobic exercise (40% maximal power) in 15 subjects (12 female and 3 male) with a polymorphism (rs37369) of a different (AGXT) genotype, which could be due to the fact that AGXT upregulated and catabolized D-BAIBA similarly during acute exercise (76), and L-BAIBA production increased, possibly due to the oxidation of the upstream species L-valine (18). This suggested that future assessment of exercise-mediated changes related to BAIBA would require special attention to isomeric differences and changes in AGXT (75, 77).

With regard to long-term exercise, in the follow-up of patients undergoing renal dialysis, plasma BAIBA levels were found to be significantly lower in sedentary patients than in those who remained physically active over long periods of time; however, there was no significant difference in the data across subjects with different levels of exercise over a long term. Unfortunately, owing to its cross-sectional nature, a causal relationship between plasma BAIBA levels and physical activity could not be established in the study (76). Morales et al. (75) reported a significant increase in serum BAIBA levels after 20 weeks of aerobic training. A study including both normal and obese adolescents showed that serum BAIBA levels increased after prolonged exercise (aerobic or resistance) regardless of obesity (78). This was confirmed by the results of an animal model, in which four weeks of hypoxic training increased BAIBA levels in the gastrocnemius and blood of obese rats (79). Roberts et al. (4) found serum BAIBA levels to be significantly higher in mice subjected to 3 weeks of free wheel exercise than in quiet control mice, and the BAIBA levels in gastrocnemius and quadriceps to be increased 5.2-fold and 2.2-fold, respectively. This suggested that exercise significantly up-regulates BAIBA levels in muscle and serum. Differences in the modulation of BAIBA between different forms of exercise would be worth noting (80). Research observed that high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) significantly upregulated the expression of HADH, ACADS, and HADHA, key genes involved in BAIBA biosynthesis, in APOE-KO mice fed a high-fat diet. The mRNA expression of HADH, ACADS, and HADHA, key genes involved in BAIBA biosynthesis, was significantly upregulated in the HIIT group. Interestingly, after two weeks of single-leg immobilization, the femoral artery and femoral plasma concentrations in each leg were significantly higher in healthy male subjects at rest and during knee extension exercise in both legs. Venous plasma BAIBA concentrations were increased, but static-exercise BAIBA concentrations were decreased after leg immobilization (39). This pulsatile pattern of release and uptake may be a result of BAIBA uptake by skeletal muscle and may also be related to the metabolism of thymidine as a result of exercise.

In summary, although the modulatory effects of acute exercise on BAIBA levels have been studied relatively less, different forms of long-term exercise significantly increased BAIBA levels in serum and skeletal muscle, and HIIT has a more significant upregulation effect on serum and skeletal muscle BAIBA However, comparisons between different forms of exercise are currently scarce; therefore, the effect of factors, such as intensity, duration, and rest, on BAIBA levels would need to be explored further, and the question of whether exercise regulates synthesis and breakdown of BAIBA or uptake of BAIBA by skeletal muscle will be central to uncovering the relationship between exercise and BAIBA.

Little is known about the mechanisms by which BAIBA mediates exercise to regulate metabolism. 2022 research showed that BAIBA levels are reduced in hypoxic environments, whereas BAIBA expression is increased in blood and gastrocnemius muscle of mice after hypoxic exercise and was positively correlated with inguinal fat PPARα expression levels (81). Notably, both the hypoxic environment and hypoxic exercise upregulated PPARα mRNA expression in adipose tissue (81). Whether hypoxic exercise, as an effective form of fat loss, can promote fat metabolism by regulating adipose PPARα levels through BAIBA, and the mechanism of hypoxic environment being an external stimulus in BAIBA production during exercise would be important directions for future research towards revealing the mechanism of hypoxic exercise for weight loss.

To date, studies have shown that moderate exercise produces ROS, which promotes AMPK activation. Intense exercise, on the other hand, impairs mitochondrial function and inhibits AMPK activity and expression. Antioxidant supplementation may ameliorate the damage caused by excessive ROS production from intense exercise, but it counteracts the beneficial effects of moderate exercise at the same time, resulting in two incompatible interventions (82). A recent study comparing exercise and antioxidant interventions in T2DM rats found that moderate exercise can promote redox reactions in the liver by increasing antioxidant capacity. In contrast, antioxidant interventions impair redox homeostasis by inhibiting oxidative stress (82). It is interesting to note that BAIBA acts as a signaling metabolite and antioxidant, regulated by exercise; this has been validated at multiple levels (animal, cellular, protein, and genetic) (72–74). The validation of AMPK as a downstream target of BAIBA suggests that BAIBA supplementation may generate moderate ROS and serve as a suitable intervention to promote redox homeostasis while avoiding the damage caused by intense exercise (82).

Studies have shown that BAIBA plays an important role in health, not only by effectively improving glucose and lipid metabolism, but also by improving bone homeostasis and downregulating inflammatory responses and oxidative stress. A number of these effects appear to parallel benefits obtained via exercise-generated BAIBA, suggesting that BAIBA could potentially be applied as a drug or exercise mimetic.

In clinical applications, it is important to achieve drug efficacy without toxic side effects. A toxicological study showed that L-BAIBA can be delivered without adverse effects at 900 mg/kg/day for 90 days, which is the highest level tested (83). In addition, in human studies, approximately 2–20% Caucasians and 50% Asians were found to be deficient in AGXT2 (84, 85), with high urinary D-BAIBA levels. Kittel et al. (86) detected three-fold higher plasma BAIBA concentrations in a small number of subjects with AGXT2 gene deficit; however, none of the studies reported any adverse effect of increased endogenous BAIBA, suggesting that endogenous and exogenous factors resulting in high plasma BAIBA levels do not have any pathological effect (87). Notably, in pathological situations with substantial DNA degradation, such as malignancy (84, 88), radiation (89), and short-term starvation (90), the levels of BAIBA in urine are elevated. However, the current study was unable to define a causal relationship between BAIBA and these pathological conditions, and given that BAIBA inhibits oxidative stress in cancer cells (13), the feedback elevation of BAIBA was speculated to be a protective strategy of the body itself, thereby providing a theoretical basis for the clinical application of BAIBA as a new drug.

Although BAIBA can be detected in both blood and urine, the time course in the two matrices may not be the same. After an intervention with the DNA-based drug BC007, plasma BAIBA concentrations were found to increase after 3 min, reached a maximum after 60 min, and declined to baseline levels (87). The same intervention led to a rise in urinary BAIBA levels within a maximum of 2−4 h and a decline to pre-intervention levels over 8–12 h. BAIBA was considered to be metabolized rapidly in plasma, with urine representing a better matrix for testing, since sampling is non-invasive and the time profile is more favorable for testing.

Wang et al. reported that D-BAIBA is predominantly synthesized in humans while L-BAIBA is predominantly synthesized in mice (45); this was consistent with the recent finding that human D-BAIBA plasma concentrations are 67-fold higher than those of L-BAIBA (77). Most studies have shown that D-BAIBA is the major enantiomer of BAIBA in human urine (4, 91). However, in the mammalian kidney, AGXT2 levels are high (71), and D-BAIBA is considered the preferred substrate (23); therefore, D-BAIBA would be difficult to detect in urine (92). Since the lowest levels of urinary BAIBA were not observed in the 24-h observation time frame, D-MMS could have been further metabolized. Therefore, detection of the catabolite D-MMS may be the next step in determining whether D-BAIBA can be used as a urinary disease biomarker.

Biomarkers are characterized by their specificity, sensitivity, stability, non-invasiveness, and reproducibility. BAIBA is considered a biomarker for osteoporosis (45), and recent studies have shown it to possibly be a biological marker for the coronavirus infection as well (67). While two histological screens showed that BAIBA specificity and reproducibility met requirements (45, 68), and non-invasive testing in urine is attractive, there are several issues regarding the detection of enantiomers and metabolic degradation of BAIBA, owing to which stability and sensitivity of assays for BAIBA as a biological marker would need to be explored further.

BAIBA is a signaling metabolite that maintains lipid homeostasis by promoting white fat browning and increasing FFA oxidation, lowers blood glucose (possibly through an insulin-independent pathway), promotes osteogenic differentiation, and reduces inflammation and oxidative stress. Exercise promotes BAIBA production in skeletal muscle and inhibits its uptake. BAIBA has effects in a variety of diseases and has become a biomarker for osteoporosis and the coronavirus infection. Exogenous BAIBA can effectively perform biological functions without causing any side effects. Thus, it may have a promising future as a drug and biomarker.

However, there are many questions still that need to be addressed in future. 1. Since most existing epidemiological and experimental studies do not distinguish between D-BAIBA and L-BAIBA, there is a need to further define the biological functions of each subtype. 2. Since osteoclasts form an important factor in bone metabolism, it would be important to explore whether BAIBA can directly mediate the number or function of osteoclasts, and what would be the mechanism involved. 3. There are only few studies that have compared the regulation of BAIBA levels by different exercise modalities, and investigated whether exercise regulates health via BAIBA; hence, the relationship between exercise and BAIBA synthesis and secretion should be explored in detail in future using different times, intensities, and exercise frequencies.

XY, YY is responsible for topic selection, frame design and writing. TL, ML, TY, GH and GW were responsible for document retrieval and chart design. BC conducted literature research and final revisions. All authors contributed to the article and approved the submitted version.