Introduction
Trimethylglycine (TMG) is a neutral zwitterionic molecule that is structurally the amino acid glycine with 3 methyl groups attached to it (9). It is commonly called as “betaine” (BET), although in chemistry a BET can be used to refer to the category of molecules with a positively charged cationic functional group bearing no hydrogen atom and a negatively charged functional group not adjacent to the cationic site (29). Because TMG was the first dietary BET discovered, named after its discovery in sugar beet, it is the most popular molecule called as a BET; therefore, the terms TMG and BET are used interchangeably (32). For the remainder of this review, TMG will be called as BET, which is the term used on supplement labels and in the literature.
Betaine is an active metabolite of the essential water-soluble vitamin choline and can be obtained from the oxidation of choline in the liver and kidneys by a 2-step enzyme-dependent reaction (37). In addition, BET can be obtained externally from food, including wheat bran (1,330 mg per 100 g), wheat germ (1,241 mg per 100 g), spinach (600 mg per 100 g), beets (250 mg per 100 g), wheat bread (200 mg per 100 g), and shellfish (218 mg per 100 g) (41). It is estimated that the average daily intake of BET in the human diet is between 100 and 300 mg (25,36). However, BET intakes can range from 1 g·d−1 to a high of 2.5 g·d−1 in individuals with diets high in whole wheat and shellfish, and supplemented dietary intakes of up to 9–15 g·d−1 are still safe (9). Betaine concentrations in human serum are normally between 20 and 60 μmol·L−1, and men tend to have higher concentrations than women (24).
In humans, BET has recently gotten much attention for its potential role as an ergogenic aid and has become a common ingredient in peri-workout dietary supplements. However, it was as early as 1952 that BET was first shown to improve general strength in patients with poliomyelitis (3). Previously, BET has also been widely explored as a dietary supplement commonly included in animal feed to enhance growth, increase muscle mass, or decrease fat mass in pigs (14,40) and in poultry (12,42). Betaine has also been used to improve recovery from exercise in untrained horses (38).
The main physiological function of BET is acting as an osmoprotectant that protects the cell against dehydration by acting as an osmolyte that increases the water retention of cells (12). Betaine also acts as a methyl donor in the transmethylation of homocysteine (39). There are several mechanisms through which BET could play a role in improving muscle strength and power. The first of these mechanisms is related to the nutrient's methyl donor properties. Betaine has been reported to increase creatine (CR) biosynthesis by providing a methyl group to guanidinoacetate using methionine (10). Similar to CR supplementation, (5,11) BET may provide a similar effect by increasing CR levels to accelerate the recycling of adenosine triphosphate (31); this can improve performance by delaying fatigue in high-intensity activities. Betaine can regulate cellular hydration and maintain fluid homeostasis through its role as an osmoprotectant. Specifically, during exercise, which is a period of osmotic stress, BET may restore osmotic balance and allow the cytoplasm to retain water (1).
Betaine may also have ergogenic effects through a favorable effect on lactate and fatty acid metabolism (1,38). Notably, BET has been shown to defend the citric acid cycle enzyme citrate synthase against thermodenaturation (4). Supplementation with BET has also been reported to elevate levels of blood nitric oxide (NO) almost 3-fold (20). The vasodilator NO could improve performance by increasing muscle blood flow during exercise and augmenting the delivery of nutrients and extraction of waste products.
Last, BET may also affect circulating hormones and muscle signaling proteins. For example, BET may enhance muscle protein synthesis by reducing homocysteine and homocysteine thiolactone. Homocysteine directly impairs insulin signaling by reducing insulin receptor substrate-1 activation, thus inhibiting Akt-phosphorylation and subsequent mechanistic target of rapamycin (mTOR) activation (26). Homocysteine thiolactone causes protein aggregation and an inactivation in protein synthetic enzymes by inhibiting insulin signaling, mRNA expression, and protein synthesis (21,28). In addition, BET has been shown to increase serum growth hormone (GH), insulin-like growth factor 1, and insulin in animals; these compounds are likely to promote protein synthesis by stimulating the mTOR pathway (6,19).
The aim of this review will be to identify the effect of BET supplementation on muscular strength and power. Strength refers to the ability to generate maximal force, where speed of movement is irrelevant. By contrast, power is the ability to generate maximal force in the shortest amount of time (15).
Methods
Experimental Approach to the Problem
This review of the literature was performed by AI by searching 3 computerized databases for peer-reviewed articles published in English since 2005. No previous systematic reviews of the literature concerning BET and muscular strength and power were identified. The research articles were searched for and selected from electronic databases, including MEDLINE (EBSCO), Scopus, and PubMed. These databases were searched using the terms BET OR TMG AND supplementation OR supplement AND strength OR power.
Subjects
Inclusion criteria for studies were those that used a placebo (PL)-controlled approach where at least 1 arm of the experimental design included BET supplementation of any form or any dose. Studies were also required to have incorporated some measure of muscle strength or power as primary outcome measures on healthy adult-aged participants (18–45 years). Exclusion was based on studies involving participants outside the chosen age range and those that incorporated cell or nonhuman animal models. Finally, studies that incorporated any population considered to be nonhealthy, such as those that tested the effects of BET supplementation on patients with different diseases, disorders, complications, or muscle skeletal disturbances were also excluded.
The initial search produced 24 citations on Scopus, 52 citations on PubMed, and 37 citations on MEDLINE. After screening for article type, text availability, publication date, language, and age of subjects, 11 articles underwent full-text review. Of these, 4 articles were excluded because the studies did not assess strength or power as outcome measures (Figure 1).
;)
Figure 1.: Flow diagram of the search strategy and results.
The primary aim was to identify randomized controlled trials (RCTs) in which a BET supplementation intervention or noninterventional control group was used. The secondary aim was to find all studies in which subjects' muscular fitness outcome of strength or power was tested.
The Physiotherapy Evidence Database (PEDro) checklist was used to assess the quality of the included studies (27), with each study receiving a score between 1 and 10. A study graded between 9 and 10 is considered “excellent,” a study graded between 6 and 8 is considered “good,” a study graded between 4 and 5 is considered “fair,” and any study graded less than 4 is considered “of poor quality” (27). All 7 studies included in this review were considered “excellent.” Refer to Table 1 for the quality scoring.
Table 1.: Quality score for eligible studies.*
Results
The length of the studies ranged from 1 to 6 weeks. All the studies administered a BET supplement, but one of the studies (13) also tested BET vs. CR supplementation, as well as the possible additive effects of CR and BET. In this study, subjects were divided into a BET-only group receiving 2 g BET per day, a BET + CR group receiving 2 g of BET and 20 g CR per day, and a PL group receiving only 20 g dextrose. The experimental groups also received 20 g of dextrose to disguise the substance and to control for any effects of the PL. The supplement dosage for the rest of the studies was 2.5 g BET per day, which is the dosage typically used in the commercial market within dietary supplements, making it practically relevant. In addition, 2.5 g is a dosage that has been shown to significantly elevate plasma BET levels and is therefore a scientifically an appropriate level of supplementation (33). In 4 of the studies, (18,23,30,35) the supplement was administered twice daily, 1.25 g each time. However, in 1 study (17) the supplement was given as a single 2.5 g dosage of BET. In all the aforementioned studies, BET was taken with a carbohydrate-electrolyte beverage/sports drink, such as Gatorade (Chicago, IL), and the sports drink alone served as the PL. Only 1 study (7) administered the supplement in capsule form, with the supplementation group taking 1.25 g BET twice per day, and the PL consisting of white flour-filled capsules of matched weight. Table 2 outlines the characteristics of each study.
Table 2.: Study characteristics.*†
One study (17) measured only muscle strength, 2 studies (18,30) measured only muscle power, and the remaining 4 studies (7,13,23,35) assessed both strength and power. The protocols used to measure these components of muscular fitness were inconsistent in the studies included in this review. To measure muscular strength, 2 studies (7,13) used the 1 repetition maximum (1RM). However, 2 other studies (23,35) measured isometric force using transducer devices, and 1 study (17) measured strength using an isokinetic dynamometer. Although a 1RM is considered the gold standard for evaluating strength, isokinetic dynamometry is often preferred because the dynamometer only allows movement to occur at a predetermined velocity, and the only variable condition is force. However, isokinetic assessment bears little resemblance to the accelerative/decelerative motion implicit in limb movement during resistance training and sporting performance (22).
To measure power, studies used vertical jump (VJ) tests (7,18,35), bench press throw (BPT) (18,23,35), bench press (BP) and back squat (BS) power output (13), Wingate anaerobic power tests (WAnT) (18), and sprint tests using an ergometer (30). Bench press throw has been recommended as the exercise for the most accurate assessment of upper-body power (16). In addition, the WAnT is considered the best indicator of anaerobic power (2). Table 3 highlights the outcome measurements of each study.
Table 3.: Strength and power outcome measures.*†
Table 3-A.: Strength and power outcome measures.*†
Most of the subjects included in these studies were relatively young, resistance-trained men. Cholewa et al. (7) matched experienced, recreationally strength-trained men between the ages of 18 and 35 into 2 groups based on training experience. The average training experience across all subjects was 4.8 ± 2.3 years, and to meet the inclusion criteria, subjects must have participated in consecutive resistance training for at least 24 months. In the studies by Hoffman et al. (17), Hoffman et al. (18), and Lee et al. (23), subjects were young men with an average age of 21.7 ± 5.1 years, 20.9 ± 3.0 years, and 21.0 ± 3.0 years, respectively, with a minimum of 3 months of resistance-training experience. In the study by Trepanowski et al. (35), the average age of all subjects was 23.0 ± 3.0 years, and they were classified as “recreationally active” resistance-trained men, but not elite-level strength-trained athletes. The study by Pryor et al. (30) was the only one included in this review to incorporate female as well as male subjects. These subjects were young and recreationally active, with an average age of 19.0 ± 0.8 years. Finally, the study by Favero et al. (13) was unique among the remainder of the studies in this review because subjects (18–30-year-old men) were not engaged in resistance training for at least 6 months before the beginning of the study.
Discussion
The purpose of this review was to evaluate the effects of BET supplementation on muscular strength and muscular power. Only 2 studies (23,30) reported significant improvements in any of the outcome measures assessed. The study by Lee et al. (23) was conducted in 12 resistance-trained men. The study was designed as a double-blind randomized PL-controlled crossover trial (RCCT), a type of RCT where each subject serves as his own control. Subjects were matched according to age, body size, and training experience before their random placements into either the BET supplementation or PL groups for 14 days. After the initial trial period, subjects underwent a 14-day washout period and then crossed over into the other 14-day period of either BET or PL supplementation. A standardized whole-body resistance-training session was performed twice during the supplementation periods to maintain the subjects' level of conditioning, and subjects were instructed to refrain from any exercise for 48 hours before the performance testing sessions. After the 14 days of supplementation, isometric BP force, isometric BS force, and BPT power were all significantly increased in the intervention group (p < 0.05), with no changes in the PL group. These increases were up to 24.61% in isometric BP force and 15.97% in BPT power. Notably, this study incorporated a high-intensity strength/power resistance exercise challenge that can be considered very demanding. Strengths of this study were that special attention was given to dietary and activity control among and within subjects. Subjects submitted 3-day diet records and 6-week activity records, and all subjects reported similar physical activity and diet before each exercise test and throughout study participation.
Pryor et al. (30) additionally reported a significant, positive effect of BET supplementation on muscle power. This study was also designed as an RCCT. Subjects were match-paired based on baseline maximum peak power and assigned to either a BET or PL group for 7 days. There was no training involved during the supplementation period. The initial supplementation period was followed by a 3-week washout phase, and then subjects were assigned to the opposite group for another 7 days. The maximum peak power during a cycling sprint test was increased by 5.75% after supplementation with BET (p = 0.007), with no difference in power in the PL group from baseline. A major strength of this study is that is was conducted in both resistance-trained males (n = 9) and females (n = 7).
The remaining 5 studies (7,13,17,18,35) reported no significant effects on any of the outcome measures for either strength or power after BET supplementation. In the study by Cholewa et al. (7), however, there was a trend (p = 0.07) for increased VJP (vertical jump power) in BET vs. PL. This study was designed as a double-blind randomized PL-controlled trial. Subjects were matched and assigned to either a BET or PL group for 6 weeks. Over the course of the study, subjects completed a nonlinear periodization training program consisting of three 2-week microcycles. Subjects performed the same exercises, sets, and repetitions during the investigation and were instructed to abstain from performing other structured exercise programs throughout the duration of the study.
In the study by Favero et al. (13), it was concluded that BET supplementation did not affect strength and power performance, whether it was alone or added to CR supplementation. The study was designed as a double-blind randomized PL-controlled trial, and subjects were randomly assigned to receive either BET, CR, BET, and CR, or a PL for 10 days. Subjects were instructed to refrain from any exercise training program throughout the study, and muscle strength and power were assessed at baseline and after the 10 days of supplementation. Although CR was shown to improve strength and power outcome measures, BET had no additive effect. Likewise, in the studies by Hoffman et al. (17,18), BET was shown to have no effect on VJP, BPT peak power, WAnT peak power, or force outputs during an isokinetic BP exercise. The first study (17) was designed as a RCCT. Subjects were randomized to either a BET or PL group for 15 days, during which subjects reported 5 occasions for a testing and training session. The initial supplementation period was followed by a 4-week washout, during which subjects only maintained their familiarity with the testing device by once per week workouts. After the washout period, subjects repeated the same 15-day exercise protocol assigned to the opposite group. The other study by Hoffman et al. (18) was designed as a double-blind randomized PL-controlled trial. Subjects were matched for size and strength and randomly assigned to either a BET or PL group for a 15-day period. After baseline testing, subjects returned for 2 days of strength and power assessment on days 7 and 8 and days 14 and 15 of the supplementation period. Finally, the study by Trepanowski et al. (35) was designed as a RCCT involving 14 days of BET or PL intake, with a 21-day washout period. Testing was conducted before and after each 14-day treatment period. Subjects were asked to maintain their usual exercise routine throughout the entire study period but to refrain from strenuous physical activity during the 48 hours before each test day. No differences were noted in any measures of exercise performance between BET and PL supplementation, and BET had no effect on either leg press (LP) or BP max isometric force or VJ or BPT power.
Because 5 of the 7 studies did not report any effect on strength or power as a result of BET supplementation, there is not enough evidence to establish a clear effectiveness of the supplement on these measures of muscular fitness. However, the ergogenic potential of BET cannot be completely ignored. Notably, 1 well-conducted study (23) did show a dramatic increase in both strength and power as a result of BET supplementation. Since this trial was the only one of the studies included in this review to incorporate a high-intensity strength/power routine, it is possible that BET works best in this type of training environment imposing high metabolic demands. Possibly under the stressful cellular conditions as a result of the intensity of the resistance exercise challenge, BET, an organic osmolyte, is able to maintain biochemical function and protect sensitive metabolic pathways, such as those involved in protein turnover, amino acid metabolism, pH regulation, and gene expression (8). Since one of the main functions of BET is to maintain cellular hydration and delay fatigue during training, the increases in strength reported by Lee et al. (23) and Pryor et al. (30) may actually be due to increases in training volume as a result of BET, as greater training volume over time can lead to increases in strength and power. However, this would likely be a chronic effect of BET supplementation and would require a longer supplementation period to manifest. In all the studies included in this review except one (7), the effects of BET supplementation were measured only acutely. Notably, when the effects of 6 weeks of BET supplementation was studied by Cholewa et al. (7), there were reported increases in BP work capacity after BET supplementation. While the increases in training volume did not translate into strength improvements in the study, this may be due to the fact that subjects were highly experienced strength-trained individuals, and the ability to make large performance gains and detect changes in strength decreases with training experience (22). Future studies should therefore also consider the long-term effects of BET supplementation on strength and power.
It is also worth noting that while BET may not play a great role as an ergogenic aid by increasing strength or power, studies have suggested that BET may promote adiposity reductions and lean mass gains. For example, in the study by Cholewa et al. (7), body composition was also measured and was shown to improve significantly in the BET but not the PL group. Subjects completed 3-day food diaries and were instructed to consume similar diets throughout the study period to control for energy and protein intake, but the lack of standard control meals was identified as a limitation of the findings. Although there may be benefits to supplementation with BET beyond strength and power, research analyzing the effects of BET supplementation on body composition and hypertrophy in humans is limited.
Another reason for the lack of consistency in the studies in this review is the great variation in outcome measurements used. Future studies should use standard measurements for assessing strength and power, and it is important to consider effects of the supplement on both the upper- and lower-body muscles. To evaluate strength, the 1RM BP and 1RM BS should be used, as the 1RM is considered the gold standard for strength assessment (22), and the BP and BS are common exercises performed by weightlifters. The BPT is recommended as the most accurate assessment of upper-body power (16), and the VJ is often considered the best measure of lower-body power (22).
Furthermore, although the dosage of BET was fairly consistent, the timing of the supplementation ranged across studies. Since the absorption of BET is rapid, with an absorption half-life of around 17 minutes after oral ingestion and plasma levels peaking after 40–60 minutes, (34) it is possible that the best effects on training will be seen if the full dosage of BET is consumed 40–60 minutes before exercise. However, in 4 of the 7 studies included in this review (18,23,28,35), the BET dosage was split as 1.25 g twice per day. Because a minimum dose of 2.5 grams may be required to elevate plasma BET levels (33), splitting the dose into 1.25 grams may not yield the same desired results. Future research should therefore test supplementation with a full dosage of 2.5 g of BET preexercise and also take into consideration whether BET dosages higher than the typical 2.5 g may provide greater benefits. Another point worth mention is the possibility of an additive effect from the carbohydrate administered with the BET. Future studies evaluating the effectiveness of BET should administer the supplement in capsule form, eliminating any confounding effect of the carbohydrate sports drink.
It is important to note that the number of studies was limited, which stresses the importance for additional research. Many of the studies were also limited by small sample sizes, so future studies should include a greater number of subjects. These studies should be designed as RCCTs, because within vs. between-group experimental designs allow for greater control of statistical variance and increase sensitivity and reliability of measures. Because most of the subjects in the studies included in this review were resistance-trained young men, this stresses the importance for future studies to consider the effects of BET supplementation in more diverse populations. These studies should incorporate women and control for sex differences and include older (>35 years) and nonresistance-trained individuals as well. Although BET may not lead to major increases in strength or power for athletes or young resistance-trained individuals, it may provide more benefit to elderly individuals experiencing the natural age-related decline in muscle strength and power. Also, in the 1 study included in this review that included female subjects (30), a significant positive effect of BET supplementation on muscle power was observed. Therefore, BET supplementation may be more effective and provide greater benefits and enhancements in performance for women than in men.
Practical Applications
This review highlights the lack of evidence for a clear ergogenic effect of BET supplementation on strength and power performance. Only 2 of the 7 studies included demonstrated a positive effect on outcome measures of strength or power as a result of BET supplementation. However, the ergogenic potential of BET cannot be completely ignored. Specifically, in a study incorporating a high-intensity strength/power resistance exercise challenge that can be considered very demanding, isometric BP force increased by 24.61% and BPT power increased by 15.97% after supplementation with BET. Therefore, it is possible that BET works best in this type of training environment, under stressful cellular conditions. However, because of the limited amount of research assessing the impact of BET supplementation on muscle strength and power, further studies are necessary to evaluate its effectiveness.
Acknowledgments
No grant aid or manufacturer's aid was received in conjunction with the present study. The author has no conflicts of interest to disclose.
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