What do we know about homocysteine and exercise? A review from the literature

Acute effect of exercise on tHcy concentrations

Many experimental studies have examined the acute effects of exercise on tHcy concentrations, by varying the degree of intensity, duration and type of exercise. Most of the reviewed articles from this category found a tHcy increase immediately after acute exercise. Konig et al. [18], found higher tHcy concentrations after 1 and 24 h of a triathlon competition. Herrmann et al. [17] found the same response after various modalities of aerobic exercises [17, 18]. These effects are in line with those found by several investigations [11, 19, 20, 22, 23, 24, 26, 41]. The study of Herrmann et al. [17], speculates that intensity and duration of exercise could determine the tHcy response, due that only marathon runners showed significant tHcy increment both, from baseline and comparing by groups. These authors suggested that the high intensity sustained by the runners comparing to the 100 km run and mountain bike race, can have more rest periods during trials, being a possible answer of this response. In contrast, other research studies including different intensities showed that the tHcy increase is independent of the intensity of the exercise [11, 24] or type of exercise [22].

Sotgia et al. [21], who compared athletes and non-athletes subjects, found no changes in tHcy after acute exercise but a decrease in the Homocysteine reduced form [21]. On the other hand, Hammouda et al. [25], did not found any change in tHcy concentrations after acute exercise [25]. This probably relies on the fact that the intervention was performed only by a 30 s Wingate test, not long enough to stimulate the methionine synthesis. Moreover, Konig et al. [18], concluded that although acute exercise significantly increases tHcy, chronic endurance exercise was not associated with higher plasma tHcy concentrations [18]. Health status from individuals can also influence the metabolic pathways [5]. But in the reviewed investigations, when analyzing active and sedentary people, acute effects had the same tHcy increment-response. Authors have suggested that intense exercise accelerates protein turnover catabolism and the pool of amino acids in the muscles [21]. As a consequence, it may lead to an increase in the catabolism of the intermediary metabolism and homocysteine formation [41].

From these results it could be observed that acute exercise generally induces an increase immediately after exercise, independently of the previous training level, intensity and duration.

Effect of chronic exercise on tHcy concentrations

Regarding the studies analyzing the effect of chronic exercise programs on tHcy concentrations, it is difficult to reach an agreement due to the variety of type of exercises and training programs. Some researchers highlighted an exercise-induced-fall in tHcy after training: the investigations of Randeva et al. [12] and Choi et al. [13] included aerobic modalities and Vincent et al. [27] and [30] performed resistance programs [12, 13, 27, 30]. Thus, we did not find the common point among these results, due to the differences in the type of exercise, training duration and sample studied.

On the other hand, three of the studies reported an increase in tHcy concentrations, although the training interventions were also different, using both aerobic and resistance exercises. The investigations of Molina-López et al. [32] and Guzel [31] found increased tHcy after training but both of them were within reference values (<15 μmol/L) [31, 32]. Interestingly, Okura et al. [29] found different responses depending on the baseline tHcy status [29]. An increased tHcy was observed after training in those within normal tHcy concentrations at baseline; in contrast, the contrary effect was observed in subjects with hyperhomocysteinemia at baseline, where tHcy decreased after training exercise programs.

On the other hand, some studies provided data that training does not alter tHcy concentrations [28].

Furthermore, health status could provoke different responses in the homocysteine metabolism than the effect on general or healthy population, as shown by Randeva et al. [12] in overweight polycystic women and by Vincent et al. [27] in elderly people [12, 27].

In summary, the studies of the effect of chronic exercise did not show a consistent effect on tHcy, neither in active nor sedentary samples, nor type, duration and intensity of exercises. Unfortunately, these observations could not be used to discuss the effect of chronic exercise on tHcy in healthy individuals or athletes. It could be observed that the intervention exercise programs used different intensities, duration of training intervention, type of exercise and study population. This could be the reason for the variability in the results and in sight of these studies; the question about the relationship between tHcy and chronic exercise remains unclear.

Relation of physical activity levels and/or cardiorespiratory fitness with tHcy concentrations

Poor cardiovascular fitness is another important risk factor for cardiovascular disease and is a predictor of morbidity and all-cause mortality [15]. Kuo et al. [14], found that tHcy concentrations were inversely associated to cardiovascular fitness in adult women but not in men, independently of body mass index (BMI), age, race, vitamins B, creatinine levels and physical activity among other factors [14].

The study conducted by Ruiz et al. [15], reported no association of tHcy with any measure of physical activity as cardiovascular fitness or physical activity level when controlling for MTHFR genotype in children. In contrast, a further study by Ruiz et al. [36] showed that cardiovascular fitness was negatively associated with homocysteine levels in young women when controlling for MTHFR genotype [15, 36]. These results are in accordance with those found by Kuo et al. [14]. Ruiz et al. [36] suggested that this negative association could be due to sex hormones modulation. Differences in rates of homocysteine remethylation [42] and estrogen concentrations [43] may contribute to the homocysteine sex dimorphism. In another investigation conducted by Dankner et al. [38], results did not show association between tHcy and cardiorespiratory fitness in adult males [38]. The review of Joubert and Manore [5], concluded that tHcy could be dependent on the individual fitness level of participants [5]. Dankner et al. [35] found a negative correlation between PA levels and tHcy in elderly, independently of the vitamin-B status and MTHFR genotype [35]. Moreover, in an investigation conducted by Nygård et al. [44], results showed that physical inactivity was associated to higher tHcy [44]. This author suggests that exercise exerts most favorable effects in subjects with hyperhomocysteinemia, as shown by Unt et al. [34], who found higher tHcy concentrations in ex-athletes returning to a sedentary lifestyle comparing to those who continued being active [34]. In this study, vitamin status or dietary habits did not reveal any difference. In contrast, Joubert and Manore [6] did not found any association between PA levels and tHcy concentrations [6]. Furthermore, they reported that individuals who had higher levels of PA had also higher tHcy concentrations and may need a vitamins B supplementation to keep blood tHcy concentrations as low as possible [6]. The intervention studies analyzing the relationship between tHcy and PA levels show some limitations as the low accuracy of the measurement of PA level by questionnaires.

Implicated biomarkers related to homocysteine concentrations and exercise

The literature has studied the relation of the known factors that influence homocysteine metabolism and its implication with exercise [6, 35]. These factors include B vitamins, such as folate, vitamin B12 and vitamin B6 blood levels as cofactors of several enzymes involved in homocysteine metabolism [7, 45]. Some authors have speculated that proper intake of vitamin B6, B12 and folate can help to maintain low tHcy concentrations and support the increased demand on metabolism during high intensity exercise [18]. The inverse correlation among serum vitamin B12, and folate is well established in the literature, but this interaction may be modulated by exercise or training. The literature shows a great variability in the correlations with folate, vitamin B12 or B6 and tHcy concentrations due, among other factors, to the lack of control in the methodology analyzing dietary intake and blood levels of vitamins B. The correlation between blood vitamin B12 and folate with tHcy before exercise has been observed in various studies [18, 46]. However, results are less clear and sometimes controversial regarding exercise or training program. Moreover, it seems that there is some consensus about the increase of folate, vitamin B12 after acute exercise, competition or training programs [11, 46]. Vitamin B6 is required as coenzyme of transaminases, decarboxylases and glycogen phosphorylase in metabolic pathways of energy production, but in contrast, results from the study of Iglesias-Gutierrez et al. [24], did not reported any relationship between vitamin B6 and substrate utilization during different intensities throughout the trials [24]. On the other hand, Herrmann et al. [17], suggest that endurance athletes had a higher prevalence of B vitamin deficiency due to the high necessity of vitamin B6 and folate not only during exercise but also during training [47] because vitamin B6 is necessary to fuel working muscles and to repair damaged tissue [5].

The C677T polymorphism of the MTHFR gene, has been established as an important genetic determinant of elevated tHcy [48]. There is evidence that physical activity may also alter homocysteine metabolism by increasing protein and/or methyl group turnover [49]. Another implicated parameter is creatine, which is responsible for a considerable consumption of S-adenosylmethionine in the liver for homocysteine formation [41]. During high intensity exercise, creatine-phosphate is required as an immediate energy source for muscle contraction. The increase in creatine synthesis demand can be a key factor in the methyl balance modulation and one of the most important factors related to increased tHcy [21]. The increased creatinine after acute exercise has been observed in different studies [21, 50]. Creatine production is parallel to tHcy elevation and in addition to the need of vitamin B6. Some authors have studied the effects of creatine supplementation followed by exercises interventions [26]. Deminice et al. reported that 0.3 g/kg of creatine supplementation during 7 days were unable to lower tHcy concentrations either at rest or after acute exercise [26]. Surprisingly, some animal research showed opposite results, founding a decrease in plasma tHcy after creatine supplementation [41, 51]. These contradictory data suggest that inhibition of the endogenous methylation demand by creatine supplementation can reduce tHcy levels in animals, but not in humans [26]. However, more studies are necessary to examine activities of key enzymes on creatine synthesis after acute exercise.