INTRODUCTION
In the 1980s and early 1990s, Tarnopolsky (117), Phillips (98), and Lemon (75) first demonstrated that total protein needs were 50–175% greater in athletes than sedentary controls. Greater protein needs have typically been determined by the nitrogen balance technique, which assesses the overall amount of protein needed based on its role as substrate in the body (7,75). Although this technique is applicable for amino acids such as lysine, whose primary role is substrate, it may not indicate what is “ideal” for additional metabolic roles that amino acids may have in ergogenic functions.
ESSENTIAL AMINO ACIDS
There are 20 total amino acids, comprised of 9 EAAs and 11 nonessential amino acids (NEAAs). EAAs cannot be produced in the body and must be consumed in the diet. Protein quality is typically determined based on the EAA profile of a given protein (131). Generally, animal and dairy products contain the highest percentage of EAAs and result in greater hypertrophy and protein synthesis after resistance training than a vegetarian protein-matched control (24,52,116).
Several studies have indicated that the EAAs alone stimulate as much protein synthesis as a whole protein with the same EAA content (90). For example, Borsheim et al. (17) found that 6 g of EAAs stimulation doubled the protein synthesis compared to a mixture of 3 g of NEAAs combined with 3 g of EAAs. Moreover, a landmark study by Paddon-Jones et al. (90) found that a 180-calorie supplement containing 15 g of EAAs stimulated more protein synthesis than an 850-calorie meal with the same EAAs content from a whole protein source. The authors suggested that the faster rate of digestion of the lower calorie EAA supplement may have elicited a more robust rise in plasma EAAs concentration than the larger, slower digesting meal. Based on the available literature, it appears that 10 g of EAAs may be required to maximally stimulate protein synthesis (34).
BRANCHED CHAIN AMINO ACIDS AND LEUCINE
The 3 BCAAs, leucine, isoleucine, and valine, are unique among the EAAs for their roles in protein metabolism (87), neural function (14,35,84), and blood glucose and insulin regulation (19). Their names are derived from their chemical structure because their side chains are comprised of branching methyl groups. The following section will address BCAA's role in anaerobic and aerobic events.
BRANCHED CHAIN AMINO ACIDS FOR MUSCLE SIZE AND STRENGTH
The BCAAs are unique from other amino acids because the rate-limiting enzymes responsible for their degradation are low in splanchnic tissues (110). Thus, orally ingested BCAAs appear rapidly in the blood stream, exposing muscle to high concentrations of these amino acids; ultimately making them unique regulators of skeletal muscle protein synthesis (87). Classic research from Garlick (43) found that BCAAs were able to stimulate skeletal muscle protein synthesis to the same degree as all 9 EAAs. Of the BCAAs, only leucine was able to independently stimulate protein synthesis. It is well known that vigorous exercise can induce a net negative protein balance in response to both endurance and resistance training (73). Norton and Layman (87) proposed that consumption of BCAAs, namely leucine, could turn a negative to a positive protein balance after intense exercise. In support, the consumption of a protein or an EAA complex that contains sufficient leucine has been shown to shift protein balance to a net positive state after intense exercise training (13,87). Furthermore, Tang et al. (116) recently reported that whey, which has 36% more leucine than soy, stimulated 33% greater protein synthesis than soy after exercise.
These findings led Norton and Wilson (86) to suggest that optimal protein intake per meal should be based on the leucine content of the protein consumed (Figure). Research indicates that 2–3 g of leucine are required to maximize protein synthesis (86,91,118). Plant-based proteins including wheat and soy have only 6–7% leucine, respectively, whereas egg and dairy products contain 9–11% leucine. To optimize protein synthesis with wheat (7% leucine), an individual may need to consume 45 g of protein, but only 27 g if using whey protein based on their respective leucine contents. Norton et al. (88) demonstrated this principle in rats where whey was superior to wheat for stimulating muscle protein synthesis. The differences in muscle protein synthesis were based on leucine content of the respective protein sources and their ability to increase postprandial plasma leucine concentrations (88).
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Figure: (a) Leucine percent of protein sources. (b) Amount of protein needed from various sources to meet 3 g of leucine.
In accordance with the signaling data, BCAA supplementation combined with resistance training has been demonstrated to increase lean body mass, strength, and decrease body fat (25,81,111). Moreover, BCAAs seem to lower soreness after eccentric exercise (60) and prevent declines in both testosterone and power after an overreaching cycle (69). BCAAs have been thought to primarily augment adaptations by acting as the primary signal to activate protein synthesis (e.g., regulation of translation initiation) (5). However, protein synthesis itself is an anabolic process requiring energy, particularly during translation elongation (129). Wilson et al. (129) have recently demonstrated that taking the BCAA leucine in between meals (135 minutes following) extends protein synthesis by increasing the energy status of the muscle cell. BCAAs may modulate protein synthesis by acting as direct signaling molecules for translation initiation and through providing energy for translation elongation. In summary, strength training athletes should focus on consuming adequate BCAA/leucine content in each of their meals through selection of high-quality proteins or BCAA supplements (129).
Although leucine is most renowned for its ability to increase protein synthesis, it has also been demonstrated to reduce muscle protein breakdown by inhibiting the ubiquitin-proteasome system, the dominant pathway for the degradation of skeletal muscle proteins (108). It is currently thought that these effects are at least partially mediated through its metabolite HMB, which is also a powerful inhibitor of the ubiquitin-proteasome system and is discussed in detail in a section below.
BRANCHED CHAIN AMINO ACIDS FOR AEROBIC EXERCISE
BCAAs have been used to lower rates of perceived exertion and enhance endurance performance. The uses of BCAAs for these purposes are based on the serotonin theory of central fatigue (14,35,84). According to this theory, during endurance exercise, plasma fatty acids increase in circulation, thereby displacing tryptophan from the albumin carrier protein. An increase in tryptophan uptake and conversion to serotonin in the brain leads to central fatigue (129). It is the ratio of tryptophan:BCAAs that determines tryptophan uptake as these amino acids compete for absorption into the brain. BCAA supplementation during endurance exercise decreases the tryptophan:BCAA ratio and lowers the perceived exertion (129). Although data are inconsistent (14,35,84), BCAA supplementation may increase time to exhaustion during prolonged cycling (14). For elite endurance athletes who train up to 12 times a week, rapid glycogen replenishment is essential. BCAAs combined with carbohydrates immediately after exercise have been demonstrated to increase the insulin response and result in greater rate of glycogen replenishment (4). It is likely that endurance athletes should follow a similar prescription as strength athletes for BCAA supplementation (Table).
Table-a: Practical Applications
Table-b: Practical Applications
Table-c: Practical Applications
BETA-HYDROXY-β-METHYLBUTYRATE AND ANAEROBIC EXERCISE
As discussed, it is known that leucine has anticatabolic and perhaps protective effects against skeletal muscle damage (138). It has been hypothesized that the metabolite of leucine, HMB, may contribute significantly to these effects (130). Research has demonstrated that HMB is able to speed repair skeletal muscle damage and augment strength, power, and hypertrophy gains after chronic resistance exercise training (130). One mechanism may be that HMB provides a readily available substrate for the synthesis of cholesterol needed to form, repair, and stabilize the sarcolemma after novel high-intensity muscle damaging exercise (130). However, recent evidence shows that HMB stimulates protein synthesis (37) and decreases protein breakdown by inhibiting the ubiquitin-proteasome pathway (108).
Most studies have concluded that HMB has a positive effect on skeletal muscle recovery and strength in untrained individuals (130). However, studies in trained individuals have been less conclusive, resulting in much debate on the effects of HMB in this population (130,137). In a recent publication, Wilson et al. (130) discussed a number of reasons why these conflicting results exist. The first is a general lack of periodized, high-intensity training in athletes using HMB. From a conceptual standpoint, it is essential to provide novel stimuli to individuals to induce either muscle damage or stimulate protein breakdown (31). Research suggests that trained individuals instructed not to change their programs do not benefit from HMB (70). These results amount to exactly what would be predicted if HMB needs a muscle damaging or wasting stimulus to be effective. The second reason why HMB may have shown small effects in trained individuals concerns the incorporation of highly variable outcome measures such as bioelectrical impedance and skin caliper measures as measures of body mass changes (100).
At this point, 2 studies that have provided adequate training stimuli in trained individuals have been conducted (85,93). The first was conducted by Panton et al. (93), who examined the effects of HMB during resistance training in 36 women and 39 men, aged 20–40 years, with varying levels of training experience for 4 weeks. Their training protocol consisted of very high-intensity loads, which were consistently adjusted as subject tolerance for a given weight increased. Because of the high-intensity nature of the protocol, the HMB group showed greater decreases in body fat (−1.1 versus −0.5%) and increases in bench press strength (7.5 versus 5.2 kg) and lean body mass (1.4 versus 0.9 kg) than the placebo group, independent of training experience. Moreover, Nissen et al. (85) conducted a 7-week high-intensity study in individuals who could bench press ≥135 kg and squat >1.5 times their bodyweight. Participants with HMB supplementation gained an average of 4.5 kg more on their bench press and 3.2 kg more on their squat when compared with the nonsupplemented participants.
In summary, we suggest that HMB has the optimum effect when an adequate training stimulus is provided. For untrained individuals, this will likely not require high amounts of volume training; however, for trained individuals HMB appears to be most beneficial only within a high-intensity resistance training program. Current research suggests the ideal dosing strategy for HMB is 3–6 g daily (38–76 mg/kg/d), with half of the dose consumed before exercise (41,85,132). When compared with postexercise supplementation, pre-exercise supplementation shows a tendency to lower muscle soreness and prevent the rise in indices of damage, such as LDH (132).
BETA-HYDROXY-β-METHYLBUTYRATE FOR AEROBIC EXERCISE
Research on HMB in endurance athletes is limited, but appears promising. Knitter et al. (67) found that HMB was able to enhance recovery and decrease muscle damage after a long run. Vukovich et al. (122,123) found that 2 weeks of HMB consumption increased time to reach V[Combining Dot Above]O2 peak (8%) and percentage of V[Combining Dot Above]O2max needed to reach the onset of blood lactic acid accumulation in elite cyclists. Although dosing studies are yet to be done on endurance athletes, it is likely that for muscle recovery 3–6 g will be beneficial (38–76 mg/kg/d).
FREE ACID VERSUS CAHMB
Previous research has supplemented HMB as the calcium salt, CaHMB. When CaHMB is supplemented, HMB peaks in plasma about 2 hours after consumption of a 1 g serving. However recent research from Fuller et al. (40) suggests that oral or sublingual administration of HMB in free acid gel form results in earlier and greater peaks (15% greater increases in area under the curve) in plasma HMB and increased total body retention (25%) compared with HMB administered as CaHMB. It is possible that greater retention and peak concentrations of HMB immediately after exercise from a free acid gel would improve protein turnover over CaHMB. However, future research will need to be conducted to elucidate the possibly exciting implications of these new findings.
BETA-ALANINE
Accumulation of H+ ions during high-intensity exercise is thought to be a major contributor to peripheral fatigue. Intramuscular concentrations of lactate and H+ rise as the individual's reliance on glycolysis increases. However, in the presence of carnosine, large amounts of lactate can accumulate without a decrease in intracellular pH, indicating its major role as an intracellular buffer (107). Although carnosine is synthesized from the amino acids histidine and β-alanine, the latter appears to be the rate-limiting substrate in carnosine synthesis (51). Supplementation with β-alanine has resulted in increased intramuscular carnosine levels (51), strength (57,58), power, and aerobic capacity (140). There appears to be a dose response for the effects of β-alanine on muscle carnosine levels. For example, 3.2 and 6.4 g of β-alanine per day increased carnosine content of the vastus lateralis by 42 and 61%, respectively (51,55). However, β-alanine administered as a single 3 g bolus results in severe paresthesia (51). Therefore, it is currently recommended to consume <1 g servings, taken every 3 hours daily to optimize performance benefits without experiencing negative side effects (133). In addition, changes in intramuscular carnosine are also dependent on the duration of supplementation, with elevations in carnosine concentrations by 58 and 80% at 4 and 10 weeks of β-alanine supplementation, respectively (51).
The effectiveness of β-alanine is likely dependent on the type of activity performed (133). In the resistance training domain, activities that stress the glycolytic system are thought to benefit, whereas those primarily stressing the ATP-PC system may not (133). For example, Hoffman et al. (58) found increases in training volume for moderately high repetition training when taking β-alanine. However, high-intensity strength training with longer rest periods (2–5 minutes) found no benefit in strength or muscle mass (65). For endurance athletes, the relative intensity they are constrained to in a given race is dependent on ventilatory and lactate thresholds. Stout et al. (112) found that β-alanine resulted in increases in both ventilatory threshold and cycling time to exhaustion. In summary, β-alanine seems to be the rate limiting substrate. Literature suggests athletes should supplement for more than 30 days to see benefits, at a minimum of 3- to 6 g doses spread out in small bolus servings throughout the day. Athletes who stress the glycolytic system may benefit to a greater extent from this supplement than those emphasizing maximum strength and power.
GLUTAMINE
Glutamine is an amino acid commonly found in products marketed to strength and endurance athletes. Glutamine is synthesized from glutamate and ammonia via the enzyme glutamine synthetase, making this amino acid nonessential in most conditions (6). Under stressful conditions, glutamine synthesis is impaired, making it conditionally essential (134). Skeletal muscle is the major tissue involved in glutamine synthesis and is known to release glutamine at high rates (46). This fact alone draws attention from athletes concerned with maintaining skeletal muscle throughout competitive seasons.
It is hypothesized that intense exercise decreases plasma glutamine concentrations (83), limiting its availability as a source of nitrogen for nucleotide biosynthesis (45) and for immune system cells, which require glutamine for energy. This hypothesis is based on in vitro work by Parry-Billings et al. (94), who found that lymphocyte proliferation is enhanced by glutamine in a concentration-dependent manner. Therefore, supplementation with glutamine may be effective for preventing immune suppression from strenuous exercise.
Research supporting glutamine use in healthy humans is limited. Findings from Parry-Billings et al. (94) suggest glutamine supplementation would benefit the athlete's immune system; however, in vivo research largely disputes this reasoning. Exercise duration and intensity influence changes in plasma glutamine. However, these are inconsistent between studies. For example, prolonged exercise such as marathons (28,95,102), triathlons (103), and long-distance cycling (101) may transiently decrease plasma glutamine concentration, remaining lower than resting levels for approximately 2–4 hours after exercise. However, Lehmann et al. (74) found that plasma glutamine was not different from resting levels after an ultratriathalon. Furthermore, when acute exercise is of high intensity and shorter duration, plasma glutamine may significantly increase (8,38,63). However, some high-intensity exercise studies have observed decreases in plasma glutamine (64,124).
It is important to understand the absolute change in plasma glutamine concentrations across various conditions. Parry-Billings et al. (96) found that plasma concentrations were reduced approximately 290 μM after a severe burn, but acute exercise typically observes reductions of only approximately 100 μM (56). The approximate decrement needed before supplemental glutamine provides a beneficial observed effect is currently unknown. To our knowledge, a definitive causal relationship between lowered plasma glutamine levels and impaired immune function after exercise has not been strongly solidified. Studies in which lowered plasma glutamine related to impaired immune function were observed in athletes who were asked to self-report infections (12,29). Furthermore, some studies have found no relationship between low plasma glutamine concentration and the occurrence of infection in track athletes (66) or swimmers (77). In fact, Mackinnon et al. (77) found that upper respiratory tract infection (71) was more prevalent among well-trained swimmers, with 56% of well-trained athletes exhibiting URTI compared with only 12.5% of overtrained swimmers. Interestingly, the well-trained athletes had 23% higher plasma glutamine concentrations compared with the overtrained swimmers, further questioning the relationship. Overall, preventing the drop in glutamine does not seeem to prevent infection (12).
Although immune function is likely unrelated to exercise-induced changes in plasma glutamine, there might be a role with muscle glycogen synthesis and whole-body carbohydrate storage. This was originally observed from Varnier et al. (119) who found that a primed constant infusion of glutamine (30 mg/kg prime; 50 mg/kg/h) promoted a net resynthesis of muscle glycogen stores not observed in a control group infused with alanine plus glycine. Researchers found that a more practical oral dose of glutamine (8 g) alone promoted storage of muscle glycogen to levels similar to an oral glucose polymer (18). When glutamine and glucose were taken together, the effect on muscle glycogen synthesis was not additive (126); however, this combination did result in a greater storage of carbohydrate in sites outside of skeletal muscle (18) (i.e., liver). Bowtell et al. (18) hypothesized this as a benefit to the athlete in the postexercise recovery period because ordinarily glycogen is preferentially restored in the muscle at the expense of liver glycogen resynthesis. The addition of glutamine to a carbohydrate drink would simultaneously restore glycogen to both tissues, with the potential benefit of prolonging glucose availability in the blood for central nervous system use. Glycogen synthesis seems to be augmented via activation of glycogen synthase mediated by cell swelling. A criticism of Bowtell et al. (18) was that the ingestion of 61 g (<100 g) of carbohydrate is a suboptimal amount needed to achieve the maximum rate of muscle glycogen synthesis over a 2-hour postexercise period (45). Furthermore, glutamine supplementation has been demonstrated to enhance glucose production during exercise (59). Therefore, glutamine may be most beneficial to athletes consuming a lower carbohydrate diet.
Another possible role for glutamine in exercise involves the disposal of ammonia. Exercise increases ammonia levels in the blood and increased ammonia has been proposed as a contributor to both peripheral and central fatigue (27). Supplementation with glutamine has been demonstrated to reduce ammonia buildup during long bouts of exercise (11). This is another aspect of glutamine supplementation that may possibly affect performance outcomes.
The possible role of glutamine with resistance training and changes in body composition are mechanistically based upon cell culture and infusion research indicating that cell volume changes may regulate changes in muscle metabolism (53). Furthermore, although glutamine infusion has been observed to increase whole-body protein synthesis, it is unknown whether this translates into elevated myofibril protein synthesis (50). In fact, the acute study by Wilkinson et al. (126) found that muscle protein synthesis was not different between an EAA solution containing glutamine and carbohydrate versus an isoenergetic CHO/EAA solution without glutamine. Colker et al. (62) found that trained athletes supplementing their diet with glutamine- and BCAA-enriched whey protein during training resulted in ∼2 kg greater gain in fat-free mass and greater gains in bench press endurance than whey protein alone. However, it is impossible to delineate whether the difference was from glutamine (5 g) or the added BCAA. A study comparing glutamine and a placebo found that glutamine supplementation during resistance training had no significant effect on muscle performance, body composition, or muscle protein degradation in young healthy adults (26).
In conclusion, supplementing with glutamine does not conclusively improve immune function or muscle protein synthesis in healthy individuals. There is evidence that glutamine may help restore glycogen, particularly when carbohydrate consumption is 60 g or less within 2 hours after exercise. The ideal prescription for glutamine is currently unknown. However, 8 g of glutamine consumed alone or with ≤60 g of carbohydrate immediately after exercise increases glycogen resynthesis. In terms of safety, acute intakes of ∼20–30 g per day seem to be well tolerated in healthy adults (46).
TAURINE
Taurine is a conditionally EAA based on its availability found in both cardiac and skeletal muscle, as well as the human diet. Taurine is considered a common sulfur-containing β-amino acid, lacking the carboxyl group normally associated with amino acids (80). Taurine is found in many energy drinks claiming performance enhancement as well as antioxidant properties (42,125,139). Taurine is also found in animal and fish sources (39). Skeletal muscle concentrations of taurine range from 50 mmol in untrained to 62 mmol/kg dry weight in endurance trained men (15,47), and is found in much higher concentrations in slow-twitch than in fast-twitch fiber types (78).
During endurance exercise, muscle taurine content will decrease from ∼1 to ∼0.8 μmol/g wet weight with a greater decline in fast-twitch muscle fibers (78). Research in rodents suggests a depletion of taurine causes impairment in skeletal muscle contractile ability (42), as well as cardiac muscle, through decreased calcium uptake and diminished neurotransmission (32). Taurine depletion seems to occur through 3 stages (32,33). First, the increase in intramuscular metabolites with exercise results in a hyperosmotic muscle cell relative to the outside plasma (16). Second, the cell swells followed by the final stage, in which expulsion moves taurine into the plasma to equalize osmotic pressure.
Early research on taurine suggested a possible carbohydrate sparing effect, which would be advantageous to endurance athletes (72). Taurine may strengthen hypoglycemic actions of insulin, inducing more efficient glucose utilization as demonstrated in rats (72); although a rare human study, Galloway et al. (42), found that 8 weeks of low-dose taurine supplementation of 1.5 g/d in overweight humans did not result in changes in skeletal muscle metabolites at rest or immediately after exercise. Other findings suggest that taurine elevates hepatic glycogen content, while decreasing blood glucose in rats, although human studies have yet to confirm this process (36).
Research by Jong et al. (61) showed that supplementation with a taurine antagonist suppressed calcium reuptake into the sarcoplasmic reticulum (32,48,61). Moreover, in healthy men, Zhang et al. (139) found that 6 g supplementation of taurine for 7 days attenuated exercise-induced DNA damage. These study results showed an increase in both time to exhaustion and maximal workload, suggesting an antioxidant and performance enhancing effect for the amino acid.
Taurine may increase force production by increasing Ca2+ release from the sarcoplasmic reticulum in addition to increasing sensitivity to Ca2+ (10). Data suggest that taurine might increase the mechanical threshold for skeletal muscle contraction, promote intracellular membrane stabilization, and increase membrane polarization (48). It is thought that taurine may be released from muscles during exhaustive exercise to counter increased muscle fiber osmolarity that occurs due to metabolic accumulation (10,33,48). Research on performance after consumption of a taurine (2 g) and caffeine (160 mg) containing beverage during exercise prolonged endurance time and decreased heart rate and catecholamine concentrations during exercise when compared with caffeine only (160 g) and without caffeine or taurine groups (44). This effect may be in part because of the ability of taurine to modulate Ca2+ storage capacity in the sarcoplasmic reticulum; therefore, stimulating the pumping rate of Ca2+ activated-ATPase pumps causes greater contraction force of the heart (44).
Although supplemental effects of taurine in humans warrant further research, the literature is clear that taurine plays essential roles in excitable tissue, such as calcium flux in and out of the cell, cell integrity, and osmoregulation. The noted glucose sparing effect as well as the antioxidant properties of taurine and its role in exhaustive exercise may be of the most significance when considering the role of taurine and exercise. Currently, the ideal dose for taurine is not known; however, 6 g/d over a week's time seems to have cytoprotective properties and performance benefits, whereas 2 g consumed before exercise may augment endurance capacity.
ARGININE
Arginine is a conditionally EAA that is synthesized from glutamine and proline (97). It has recently been commercially marketed within supplements purported to boost nitric oxide (NO). l-Arginine has diverse physiological roles including synthesis of protein, urea, and creatine, but it is the cell signaling products of its catabolism, such as NO, that have received much attention (1). The enzyme nitric oxide synthase (NOS) is responsible for the catabolism of l-arginine to NO and citrulline in endothelial cells (136), where NO causes vascular smooth muscles to relax and dilate (92). l-Arginine is the only suitable substrate for NO production in endothelial cells (105) and NO has been noted to be limited in chronic disease (99) and injury (113). Because of the low conversion rate of l-arginine to NO (1.2%) and the importance of NO in vasodilation (136), several investigations have been carried out to see if supplementing with l-arginine will improve vascular function. The first investigations of l-arginine as a health supplement were conducted in clinical populations demonstrating risk of full-blown cardiovascular disease (16). Although a review of these papers is beyond the scope of this manuscript, l-arginine supplementation has been demonstrated in type 2 diabetic patients to decrease blood pressure and blood glucose levels, increase insulin sensitivity, and spare protein catabolism during a hypocaloric diet (76). l-Arginine has also been shown to be effective in improving exercise capacity in patients with angina pectoris (30), increase blood flow in patients suffering from chronic heart failure, as well as positively influence hemodynamics and increase V[Combining Dot Above]O2max in hypertensive patients (82).
THE EFFECTS OF L-ARGININE ON ENDURANCE PERFORMANCE
It has been postulated that increased vasodilation, because of l-arginine, could lead to greater substrate use, waste removal, energy efficiency, and time to exhaustion during endurance events. Studies thus far have not demonstrated changes in limb blood flow when supplementing with l-arginine during exercise (82). However, it is important to understand that capillary recruitment is the initial vascular response to exercise. Changes in total muscle blood flow follow capillary recruitment, but are independent and, most importantly, not as influential as capillary recruitment for nutrient exchange (120,121). Although NO affects both vascular responses (blood flow and capillary recruitment) at rest, this gas may also have local effects within skeletal muscle independent of blood flow and capillary recruitment (104,120,121). For example, although NOS inhibitors during exercise have not suppressed changes in blood flow or capillary recruitment, they have impaired glucose uptake by 35% (104). Thus far, investigations have only quantified total limb flow during exercise, but research is suggestive that l-arginine supplementation may affect nutrient exchange during exercise (9). Specifically, l-arginine infusion has resulted in increased glucose uptake during exercise (79) and decreased blood lactate levels (21). Moreover, Bailey et al. (9) found that l-arginine supplementation increased time to exhaustion and decreased the o2 cost of running. These authors provided powerful evidence that l-arginine supplementation improved coupling between ATP hydrolysis and skeletal muscle force production. L-Arginine supplementation has also recently been demonstrated to increase the physical working capacity during cycling before neuromuscular fatigue is reached (22). However, the 2 studies supplementing with L-arginine in highly trained endurance cyclists did not find any changes in time to exhaustion or V[Combining Dot Above]O2 peak (79). Although data is limited, it is conceivable that chronic endurance exercise results in adaptations that make athletes' energy use so efficient that they are not limited by parameters thought to benefit from l-arginine supplementation. Overall, future studies with l-arginine should assess nutrient uptake, not just total blood flow, because total blood flow is not as sensitive or important as changes in nutritive flow.
EFFECTS OF L-ARGININE ON MUSCLE CELL SIZE AND STRENGTH
There is little information available on the cellular effects that l-arginine may have in healthy humans, particularly as it concerns variables affecting muscle size and strength. It has been postulated that l-arginine may increase skeletal muscle protein synthesis and blood flow in response to exercise. However, recent data suggest that an acute bolus of l-arginine did not result in changes in blood flow or protein synthesis after leg extension exercise (115,127). Satellite cell activation is also an essential aspect to muscle tissue growth because these myogenic stem cells donate the nuclei necessary to increase and sustain muscle size (3). Currently, it is thought that increased NO production in skeletal muscle is the first step to satellite cell activation (3). Anderson and Pilipowicz (2) observed an increase in satellite cell activation when cultured muscle fibers were exposed to l-arginine. Moreover, in pigs, l-arginine has been shown to improve protein content of muscle while decreasing body fat during long-term trials of 46 and 60 days, respectively (54,114). Shelmadine et al. (106) were the first to show indications of the cellular effects from l-arginine in humans. They observed elevations in skeletal muscle markers of satellite cell activation and overall DNA in recreationally trained individuals when supplementing with NO-Shotgun. Furthermore, subjects demonstrated an increase in 1 repetition maximum bench and fat-free mass after 4 weeks. Unfortunately, it is impossible to attribute the results to l-arginine alone because NO-Shotgun also contains other dietary nutrients known to increase protein synthesis and satellite cell activation, such as leucine (49) and creatine (89). From an acute standpoint, supplementation with 6 g of l-arginine 1 hour before exercise has resulted in increased peak torque on an isokinetic dynamometer (106) as well as improved power during supramaximal cycling exercise (20). Finally, a study by Campbell et al. (23) found that l-arginine supplemented alone for 8 weeks resulted in significant increases in strength and power. However, these researchers did not see any positive changes in body composition.
L-ARGININE DOSING
In a recent review, it was concluded that 3 of 5 studies found positive effects on acute changes in performance (power, strength, fatigue resistance), whereas 4 of 8 studies have found positive chronic effects while using the supplement (1). Supplementing with 6 g of l-arginine 45 minutes before training caused improved performance, but improvements were lost when retested 24 hours later without further supplementation (109). These findings suggest that acute changes in NO availability mediate the effects of l-arginine. Therefore, discrepancies in the literature may be an artifact of varying dosing protocols. Research suggests that the effects of l-arginine on performance are greatest when large doses (e.g., 6 g) are administered within 60–90 minutes before exercise (9) because this is the time l-arginine peaks. However, the same 6 g spread out in 3 small doses throughout the day did not result in changes in performance or NO byproducts (68). This may be because of the low bioavailability (∼50%) of exogenous arginine and preliminary data suggests that very little exogenous arginine is used for NO synthesis (135). Moreover, although short-term arginine supplementation (3–4 weeks) increased vascular function, these changes seem to diminish after 6 weeks, and may actually decrease blood flow, vascular function, and walking performance by 6 months (128). Negative chronic changes after supplementation are likely the result of downregulation of various NOS enzymes (128).
In summary, l-arginine supplementation may improve endurance performance in untrained to moderately trained individuals. Its effects on elite endurance athletes require further study, particularly because of their already high levels of efficiency. Although inconsistent, l-arginine may also benefit athletes seeking increases in strength and power; however, its effects on body composition are inconclusive. It is likely that to see positive effects of l-arginine, athletes will need to optimize its acute effects with the hope of obtaining chronic adaptations. Thus far, the literature seems to indicate that to do so, single large (e.g., 6 g) doses administered 60–90 minutes before exercise should be given. Moreover, to avoid downregulation of NOS enzymes, and thus NO production, individuals should only use l-arginine on their most important workouts and should consider cycling off every 3–4 weeks of use.
CONCLUSIONS AND PRACTICAL APPLICATIONS
The purpose of this paper was to provide an analysis of the possible ergogenic effects of EAAs, BCAAs, arginine, taurine, glutamine, β-alanine, and the leucine metabolite, HMB. A summary of our conclusions and practical applications can be found in the Table. In summary, for strength athletes, there is strong evidence that supplementation of 8–10 g of EAAs, or 3 g of leucine combined with 1.5 g of isoleucine and 1.5 g of valine before exercise and between meals may maximize protein synthesis, and consequently increase hypertrophy, strength, and power. To speed recovery from muscle damaging exercise and lower protein degradation, athletes can benefit from consuming 3–6 g of HMB daily with half of the dose consumed before exercise. It is important to note, however, that the benefits of HMB are most notable when athletes are presented with unaccustomed training stimuli or are exposed to a catabolic or calorically restricted state. For the athlete seeking an overall increase in total volume performed during a moderately heavy resistance training load, 3–6 g daily of β-alanine may be beneficial. However, for those seeking maximal strength, this supplement may not be ideal. Although the effects of glutamine on immune function are unclear, it appears that 6–8 g consumed after exercise when carbohydrates are consumed in very low to moderate amounts may augment the resynthesis of glycogen. Data on l-arginine supplementation are unclear in resistance training. However, limited research suggests that 6 g consumed 60–90 minutes before exercise may enhance ATP formation and, subsequently, increase strength and power.
For the endurance athlete, a similar prescription of EAAs and BCAAs may speed repair from high volume training and prevent against overreaching and overtraining. Moreover, BCAAs consumed during an endurance training session may decrease the rate of perceived exertion, and possibly increase time to exhaustion. Endurance athletes seeking to improve their lactate and ventilatory thresholds, physical working capacity before neuromuscular fatigue, and buffering capacity may consider combining 3–6 g daily of both HMB and β-alanine. Moreover, recent data seem to indicate that 2–6 g daily of taurine supplementation alone or in combination with caffeine may improve endurance performance, excitability of muscle tissue, and time to exhaustion. Finally, l-arginine supplementation, consumed 60–90 minutes before exercise in untrained or moderately trained endurance athletes may improve running economy and efficiency of ATP coupling. It is cautioned, however, that athletes only take arginine with their most important workouts and cycle the supplement (4 weeks on, 2–4 weeks off) before reusing it.
Ultimately, it is important to understand that the effectiveness of any amino acid supplement is clearly dependent on the interaction between the sport type, training status of the individual, and the overall nutrition status of an athlete (e.g., caloric deficit/surplus, high/low carbohydrate). Although these conclusions present an overview of the recommendations based on current research, each athlete should be considered on an individual basis for the need to supplement with additional amino acids.
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