All living cells use adenosine triphosphate (ATP) as a source of energy. This universal energy currency is driving the biological reactions that allow cells to function and life to exist. ATP plays a crucial role in muscle health (Jäger et al., 2021), and supplementation with ATP may improve athletic performance through increasing blood flow to the exercising muscle (Jäger et al., 2014), providing needed nutrients, and reducing fatigue.

Orally administered ATP is rapidly metabolized and acute supplementation with enteric-coated ATP is not bioavailable (Arts et al., 2012). However, oral supplementation with ATP results in increased capacity to synthesize ATP in red blood cell pools (Jäger et al., 2014). During times of increased energy expenditure, ATP supplementation has been shown to prevent declines in ATP levels, providing additional energy and delaying fatigue (Purpura et al., 2017).

A recent review of studies where oral ATP was supplemented has shown multiple benefits like cardiovascular health, muscular performance, body composition, and recovery while attenuating muscle breakdown and fatigue (Jäger et al., 2021). In a study where 12 weeks of resistance training exercise was combined with 400 mg of disodium ATP supplementation in healthy, resistance-trained males, ATP supplementation resulted in significantly greater increases in lean mass, muscle thickness, maximal strength, and vertical jump power in comparison to exercise alone (Wilson et al., 2013). In addition, ATP supplementation was able to attenuate losses of strength and power and reduced muscle damage during a two-week overreaching period (Wilson et al., 2013). In another study, 15 days of 400 mg disodium ATP supplementation resulted in better maintained performance during the latter bouts of repeated bouts of maximal cycling performance compared to placebo supplementation (Purpura et al., 2017).

While certain ergogenic sports supplements, like creatine (Kreider et al., 2017) or beta-alanine (Trexler et al., 2015), need to be consumed daily for several weeks to increase athletic performance, a recent study has shown that ATP works acutely (Freitas et al., 2019). Thirty minutes after ingestion, participants completed a series of half-squat repetitions at 80% of their 1RM, and in comparison, to placebo supplementation, the total weight lifted was significantly increased in the ATP group compared to the placebo group. Acute ATP supplementation has also been shown to improve blood pressure in hypertensive women after just a single dose of 400 mg. The test subjects performed 30 mins of aerobic exercise at 70–75% of their individual maximum heart rate. ATP induced faster recovery of heart rate variability and reduced systolic blood pressure after aerobic exercise (Freitas et al., 2018).

Most recent studies have supplemented disodium ATP at 400 mg while earlier studies used lessor amount. However, the optimal and minimally effective dose of ATP to increase exercise performance is currently unknown. Therefore, the current study was designed to investigate asministration of acute dosages of either 100, 200, or 400 mg of ATP disodium supplementation on resistance exercise, which was conducetd until movement failure, and when compared to placebo, determine a minimally effective dosage.

In comparison to placebo, 400 mg ATP significantly increased the number of set 1 repetitions (11.1 ± 0.4 vs. 12.3 ± 0.4, +13%, p = 0.04, see Figure 3), and numerically increased total repetitions (27.2 ± 0.9 vs. 28.9 ± 0.9, +6.3%, p = 0.19, see Figure 4) and total weight lifted (3,842.8 ± 121.6 kg vs. 4,060.5 ± 121.6, +6%, p = 0.22, see Figure 5). Two hundred mg ATP numerically increased set 1 repetitions (11.1 ± 0.4 vs. 11.5 ± 0.4, +4%, p = 0.47), while 100 mg ATP increased set 1 repetitions by 3% over placebo (11.1 ± 0.4 vs. 11.4 ± 0.4, p = 0.63, see Figure 3). Two hundred mg and 100 mg had no effect on total repetitions and total weight lifted (see Figures 4, 5).

Supplementation at 100 mg ATP (−4%, p < 0.05) and 400 mg ATP (−4%, p = 0.11) decreased the perceived rate of exertion compared to placebo and compared to 200 mg ATP (p < 0.05) (see Figure 6).

None of the participants reported any adverse gastrointestinal effects from ingesting either the ATP dosage or placebo.

The prevention of declines in ATP pools during times of increased energy needs through oral supplementation of ATP allows athletes to maintain performance through longer periods of exertion and consequently delay the onset of fatigue (Purpura et al., 2017). Chronic ATP supplementation in combination with resistance exercise further increases the beneficial effects of exercise on strength, power, and body composition (Wilson et al., 2013). Our dose response study confirmed previous findings, that a single-dose of 400 mg ATP 30 mins prior to exercise can increase performance during lower-body resistance exercise in recreationally trained men (Freitas et al., 2019). Lower doses failed to show significant performance benefits, but showed a beneficial effect on the rate of exertion with 100 mg ATP supplementation compared to placebo.

Previous studies investigating the effects of chronic ATP supplementation on athletic performance differ in the training status of the participants, the timing of the supplementation, and the type of exercise (Jordan et al., 2004; Rathmacher et al., 2012; Wilson et al., 2013; Purpura et al., 2017). Rathmacher et al. (2012) reported that 14 days of 400 mg/day ATP supplementation led to improved ability to maintain a higher force output during the final 10 repetitions of an exhaustive 50-repetition exercise bout. In contrast to our study, participants did not consume ATP on the day of the tests, and they did not observe any improvements in performance in early sets (Rathmacher et al., 2012). Low-dose ATP supplementation (150 or 225 mg enteric-coated ATP per day) for 15 days in untrained individuals with the final dose being taken 3 hours prior to exercise increased total bench press lifting volume as well as within-group set 1 repetitions to failure (Jordan et al., 2004). In another study, 400 mg of ATP taken for 15-days, with the final dose taken 30-mins prior to exercise has been shown to increase early set performance in a repeated sprint cycling exercise, as well as reducing drops in performance in later bouts (Purpura et al., 2017).

Possible mechanisms by which single-dose ATP supplementation enhances resistance exercise performance include changes in blood flow (Jäger et al., 2014), increasing intracellular calcium influx (Sandonà et al., 2005), preventing exercise-induced declines in ATP levels (Purpura et al., 2017), and increased energy expenditure (Freitas et al., 2019). Exercise increases blood flow to the exercising muscle, providing nutrients and oxygen and removing waste products. Changes in blood flow produce “shear stress” on the endothelial cells lining blood vessel walls, causing the cells to release ATP, which activates receptors on nearby endothelial cells (Khakh and Burnstock, 2009). The cells respond by releasing nitric oxide, which makes the vessels relax (Jäger et al., 2021). Supplemental ATP has been clinically shown to further increase this natural response to exercise. Twelve weeks of 400 mg of ATP supplementation significantly increased blood flow and significantly enhanced brachial artery dilation following resistance exercise (Jäger et al., 2014). Muscle fatigue and a reduction in force production is linked to reduced calcium release by the sarcoplasmic reticulum and by binding to the P2X4 receptor, ATP increases intracellular calcium influx (Sandonà et al., 2005). Supplementation with ATP might delay the reduction of calcium release during muscle contractions, improving muscle strength production. While ATP has been shown to act through multiple mechanisms as described, in our study acute administration likely works through a more immediate response in red blood cell ATP pools and blood flow to the muscles.

Limitations of the present study include the lack of dietary control, since the habitual food intake in the last 24–48 h are a risk of bias involved in the analyzed variables, and the lack of assessments on calcium influx or blood flow, another potential mechanism by which ATP could increase lower-body resistance exercise in recreationally trained men and the lack of post-exercise heart rate measurements, as a more objective measure of rate of perceived exhaustion. Future studies could investigate if the acute physical performance benefits translate to acute cognition benefits, as ATP production and utilization play a major role in cerebral bioenergetics and brain function (Du et al., 2018), and if the benefits seen in weight trained athletes translate into endurance type exercise, or older populations. In addition, further studies could test if the observed improved perception of exertion with the low 100 mg dose used during a chronic supplementation protocol might allow athletes to train harder and more frequently, resulting in faster training adaptations and increased training benefits. More well-design studies are needed to corroborate the presented findings.

Therefore, our findings confirmed that acute supplementation with 400 mg ATP increased performance in recreationally trained males during lower body resistance exercise, however, more research is needed to investigate if the numerical changes observed in the lower dose groups might translate in meaningful long-term performance benefits, when supplemented chronically in combination with resistance training exercise.

The effective dose of acute oral ATP supplementation during resistance exercise to increase performance was determined to be 400 mg.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethics Committee of the Federal University of Piaui. The patients/participants provided their written informed consent to participate in this study.

FR, RJ, MP, JF, and JR: conceptualization. FR and HS: investigation. JR: statistical analysis. RJ and FR: writing—original draft. All authors have read and agreed to the published version of the manuscript.

This study was funded by TSI USA LLC, Missoula, MT, USA. The funder was not involved in the collection of data or the decision to submit it for publication.

RJ and MP were employed by company Increnovo LLC. JR was employed by company MTI BioTech, Inc. This study received funding from TSI USA LLC, Missoula, MT, USA. JF is employed by TSI. RJ and MP are paid consultants to TSI. JR was involved in the study design and statistical analysis of data. JF and MP were involved in the study design. RJ was involved in study design and writing of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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