The A to Z of Effective & Less Effective Immuno-Nutrients to Prevent and Combat Respiratory Tract & Other Infections

Teddy bears are like vitamin C and zinc. They can help you when you are already sick, but what are supplements athletes and gymrats take in advance to survive the flu season without getting sick at all?

Specifically during the winter time, hard working athlete and manic gymrats can be particularly susceptible to all sorts of infections. To help you having to work out with a handkerchief in your hand all winter long, I have compiled a non-comprehensive list of supplements that may help you to maintain and even improve your immune defenses and thus to survive the cold and dark winter times without catching a cold or even the flu.

In their recent review in the Journal of the International Society of Sports Nutrition Vinicius Fernandes Cruzat, Maurício Krause and Philip Newsholme reviewed the extensive literature on nutritional supplements that act as immuno-nutrients, may to reduce immunosuppression and excessive inflammation in hard-training athletes and gymrats like yourself (or yourself in 2015 ;-)

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In said paper, the researchers from the CHIRI Biosciences Research Precinct at the Curtin University in Perth and the Laboratory of Cellular Physiology at the Federal University of Rio Grande do Sul in Porto Alegre focus what they call the "key immuno-nutrients" L-glutamine, L-arginine, branched chain amino acids (BCAA) and whey protein. Now this would not be the SuppVersity if I didn't go beyond this list and added a few more or less promising extra supplements to the list. Before we get to any of those extras, let's briefly recap what Cruzat et al. (2014) found:

"Although a balanced diet with high quality and sufficient quantity of nutrients is essential, there is growing evidence that some non-synthetic supplements can assist optimal nutrition. In fact, the use of nutritional supplements especially the provision of amino acids, has grown year-on-year. [...]

The use of proteins and amino acids for supplementation deserves special attention, since these molecules are critical for anti-oxidant and fuel provision, participating in the whole-body energy homeostasis, growth, development, recovery and immune responses.

As Cruzat et al. point out, the key targets for immunonutrition may include provision of key metabolites for immune cells per se. In other words: Immuno-nutrients feed the immune system and don't suppress but optimize the multi-layered immunte response consisting of

• the inflammatory response and cytokine release, 
• the production of chaperone proteins such as the heat shock proteins (HSPs), 
• changes in the redox balance (including glutathione, GSH metabolism), and 
• the protection of skeletal muscle mass (see Figure 1). 

Thus your reasons to consume immuno-nutrients go well beyond warding off the common cold and encompass (a) performance improvements, (b) the general strengthening of the immune system and (c) the shortening of the exercise recovery period (Nieper. 2005).

Figure 1: Biphasic immuno-inflammatory response to severe exercise and the possible immunonutrition role. Immuno-inflammatory response induced by severe exercise or heavy periods of training and the proposed role of specific nutrients with immune benefits, also called immunonutrition (Cruzat. 2014).

In that, the most widely used supplements are vitamins and minerals. Reliable evidence for their immuno-protective effects, however is scarce and the results are ambigious:

• Vitamin C: South African ultramarathon runners did demonstrate that vitamin C (but not E or beta-carotene) supplementation (about 600 mg day7 1 for 3 weeks) was related to fewer reports of upper respiratory tract infections (URTI) symptoms (Peters 1983, 1990, 1993, 1996; Peters-Futre, 1997).
  
  

  

  Classic ROS-scavengers like vitamin C are not just ineffective, when it comes to countering the increased susceptibility to infection they have also been shown to hamper the adaptational response to exercise | read more.

  These beneficial effects have yet not been replicated by other research teams. Himmelstein, Robergs, Koehler, Lewis and Qualls (1998), for example, reported no alteration in URTI incidence among 44 marathon runners and 48 sedentary individuals randomly assigned to a 2 month regimen of 1000 mg /day of vitamin C or placebo. And in view of the fact that most randomized, placebo-controlled studies have been unable to demonstrate that vitamin C supplements modulate immune responses following heavy exertion (Nieman et al., 1997b, 2002b; Nieman, Peters, Henson, Nevines, & Thompson, 2000b), it should be clear that vitamin C must not be counted among the highly effective immune nutrients. 

Zinc + C, not protetive, but effective? While the evidence supplementing with a combination of vitamin C and zinc would protect you from upper respiratory tract infections (URTIs) is scarce, there are studies like Maggini et al. (2012) which indicate that the provision of a combination of 1000 mg vitamin C plus 10 mg zinc in patients with the common cold will lead to a nonsignificant reductionof rhinorrhoea duration (range 9 – 27%) was seen. Moreover, a pooled analyses of the two studies Maggini et al. conducted shows that "vitamin C plus zinc was significantly more efficient than placebo at reducing rhinorrhoea over 5 days of treatment" (Maggini. 2012). Furthermore, symptom relief was quicker and the product was well tolerated. Despite the fact that the subjects in these experiments were ordinary people, upping your zinc and vitamin C intake, when you've already caught a cold may help you to recover faster and thus get back to the grind earlier.

• Vitamin E: As Niemann et al. point out in their review of the efficacy of various immuno-nutrients, vitamin E functions primarily as a non-specific, chain-breaking antioxidant that prevents the propagation of lipid peroxidation. The vitamin is a peroxyl radical scavenger and protects polyunsaturated fatty acids within membrane phospholipids and in plasma lipoproteins.
  
  The effect of vitamin E supplementation on the inflammatory and immune response to intensive and prolonged exercise is largely unstudied and equivocal. Cannon et al. (1991) found that vitamin E supplementation of 800 IU/day for 48 days attenuated endotoxin-induced IL-6 secretion from mononuclear cells for 12 days after running downhill on an inclined treadmill. Singh et al. (1999) showed no effect of vitamin E supplementation (4 days, 800 IU/day) on the increase in plasma IL-6 following a 98 min treadmill run at 65 – 70% V_ O2max to exhaustion. Petersen et al. (2002) reported no influence of vitamin E and C supplementation (500 mg and 400 mg, respectively, for 14 days before and 7 days after) on the plasma cytokine response to a 5% downhill 90 min treadmill run at 75% VO2max.
  
  

  

  Figure 2: Chronic supplementation with 800 IU of vitamin E (as alpha-tocopherol) has significant negative effects on markers of lipid oxidation and inflammation in triathletes (Nieman. 2004).

  A 2004 study in the course of which triathletes competing in the Kona Triathlon World Championship race event received 800 IU/day of a-tocopherol for two months does even indicate that vitamin E can increase the degree of exercise induced lipid peroxidation and the amount of several cytokines in the blood following a triathlon.Against that background and in view of the previously cited ambiguous results, Niemann et al. (2006) rightly conclude that "vitamin E supplementation to counter immune suppression and oxidative stress in endurance athletes cannot be recommended" (Niemann. 2006).
• Vitamin D: For vitamin D a slightly different image emerges. It appears to be indisputable that athletes with low vitamin D levels are at higher risk of upper-respiratory tract infections - specifically during winter times (He. 2013).
  
  The results of clinical trials investigating the benefits of vitamin D supplementation, however, are less unambiguous. In non-athletes, the monthly administration of 100 000 IU of vitamin D did not reduce the incidence or severity of URTIs; and that despite the fact that the supplement brought the 25OHD levels of the healthy subjects up, significantly (Murdoch. 2012). A meta analysis by Bergman et al. (2013), however indicates that "vitamin D has a protective effect against RTI, and dosing once-daily seems most effective".
  
  

  

  Figure 3: Length of time to viral infection related to initial serum concentration of 25-hydroxyvitamin D.
  Shown are the results of the pharmacodynamic model relating 25-hydroxyvitamin D to length of time before a viral respiratory tract infection (Bergman. 2013)

  Bergamn et al. do yet also point out that "[d]ue to heterogeneity of included studies and possible publication bias in the field, these results should be interpreted with caution" (Bergman. 2013). Against that background it may be a good idea to at least make sure that you are in the "normal range" for vitamin D - irrespective of the fact that low levels may rather be a marker than a trigger of an increased susceptibility to infections that results from uncontrolled inflammation (vitamin D as a negative acute phase reactant | cf. Waldron. 2013).

Next to vitamins, many studies have described the use of proteins, such as whey for supplements or isolated amino acids like glutamine (Kreider. 2008; Cury-Boaventura. 2008).

Simply eating enough: It may sound funny, but in the end it's not surprising that a lack of readily usable energy makes you more susceptible to infections. Firstly, a general calorie restriction is often related to an insufficient intake of important micronutrients (Pendergast. 2002). And even if the intake of all micronutrients is adequate. Important immune factors such as glutamine are (ab-)used as a substrate to produce glucose in the liver and are thus no longer available to "feed" your immune cells. Accordingly it should not surprise you that Niemann and Bishop highlight in their review of "nutritional strategies to counter stress on the immune system in athletes" that the existing data indicates that "physiological stress to some aspects of the immune system is reduced when athletes use carbohydrate during intense exertion lasting 90 min or more" and their own experiments suggest that this means "that athletes using carbohydrate beverages during competitive events will lower their risk of sickness afterwards" (Nieman. 2006).

Figure 4: Mechanisms involving whey proteins as a source of different immunonutrients. (Cruzat. 2014).

In their previously cited review, Cruzat et al. included a nice graphical overview (Figure 4) of the mechanisms by which complete proteins and peptides and their individual amino acids effect the immune system of hard training athletes.

As you can see in Figure 4, Cruzat et al. put a particular emphasis on whey protein - for good reasons.

Firstly, whey contains all the "good" amino acids of which previous studies indicate that they may have direct beneficial effects on the immune system:

• Glutamine: As Cruzat et al. point out, "L-glutamine is probably the most widely recognized immuno-nutrient since it can be used as an oxidizable fuel, a substrate for nucleotide synthesis, a modulator of intermediary metabolism of amino acids, HSP expression and a component of GSH-mediated antioxidant defense" (see Figure 5 | Cruzat. 2014).
  
  Put simply glutamine is the food your immune cells thrive on. Accordingly scientists, athletes and coaches have speculated ever since the early 1990s that supplemental glutamine should be able to prevent the exercise induced immune impairments.
  
  

  

  Figure 6: 5g of glutamine per day led to significant reductions in the occurrance of infections in marathon, ultra-marathon, mid distance runners and rowers (Castell. 1996a).

  Why? Well, exercise depletes the amount of circulating glutamine and will thus "steal" the fodder your immune cells need to survive and function (Wernerman. 2008).
  
  And in fact, there are studies that support the logical conclusion that the repletion of the glutamine that has been burned as alternative fuel during a workout with 0.1 g/kg body weight ameliorates the exercise induced reduction of lymphocytes, and could thus eventually reduce the risk of URTI’s (Castell. 1997).
  
  In that, I deliberately used the conditional, because subsequent studies with fixed (20–30 g/day) or variable (0.3 - 0.5 g/kg body wt) doses of glutamine did not report similar outcomes (Castell. 1996b; Krzywkowski. 2001; Hiscock. 2002). Accordingly, Castell et al. write in their contribution to the BMJ A-Z Supplement review (ed. Newsholme. 2011):
  

  "Overall, there is no consensus or unifying concept to explain the efficacy of exogenous provision of glutamine alone on performance in athletes, although in combination with carbohydrate or other amino acids, significant improvements have been reported." (Newsholme. 2011)

  In other words: Benefits can't be guaranteed, but specifically when glutamine is ingested in amounts of at least 20g/day in addition to carbohydrates and protein supplements it appears as if it could be a useful dietary supplement for hard-training athletes.

Where are all the other supplements gone? As I wrote in the introduction, this list is not supposed to be comprehensive. Furthermore, agents like quercetin, beta-glucan, curcumin or astragalus may be backed by animal studies, their efficacy in human beings does yet warrant further testing - specifically in athletes (Nieman. 2006). Other supplements such as the often-used herb Echinacea purpurea have been shown to fail to stimulate the nonspecific immune response and may be useful only when you are already sick or if the preperations are administered intravenously (Schwarz. 2002).

• Arginine: No, this is not a mistake. L-arginine is in fact the #2 on the list of supplemental immune modulators for hard-training athletes. Needless to say that it's not arginine itself, but rather Nitric Oxide (NO) which acts as a mediator of inflammation and immune system activation in the human body (Krause. 2011 & 2012).
  
  As a SuppVersity reader, you know that arginine has little ergogenic effect. It has beneficial effects in diabetics and may offer benefits for people who want to control their blood pressure. As a immuno-modulator, however it is similarly ineffective as it is as an ergogenic. Benefits can only be expected if the blood levels of arginine are depleted and that is - even with heavy exercise - usually not the case.

Whey protein, however, is more than the sum of its amino acid parts. Yes, whey can contain up to 26% of BCAA, plus L-arginine, L-lysine, L-glutamine.

Figure 7: Effect of maltodextrin (filled square) and maltodextrin plus hydrolyzed whey protein enriched with glutamine dipeptide (filled triangle) supplementation on exercise-induced loss of membrane integrity and depolarized mitochondria in lymphocytes and neutrophils, which are essential for the response against viral infections, such as upper respiratory tract infections (URTI), in athletes after intense training (Cury-Boaventura. 2008).

Whey does yet also contain a range of powerful proteins / peptides, namely betalactoglobulin, alpha-lactalbumin, bovine serum albumin, lactoferrin, immunoglobulins (e.g. IgA), lactoperoxidase enzymes, glycomacropeptides, as well as vitamins such as vitamin D, and minerals such as Ca2+, of these...

• lactoferrin and lactoferricin, demonstrate direct anti-microbial activity and may thus protect you from infections,
• lysosome, lactoperoxidase and diverse globulins and peptides in whey provide a synergistic protective “cocktail” activity against viral and bacterial organisms (Ha. 2003), and
• sulphur-containing amino acids, such cysteine and taurine attenuate the reduction of intracellular GSH concentration induced by intensive exercise (Lands. 1999). 

For all three of them, it is yet not fully established to which extend they contribute to the proven immune-modulating effects of whey (note: the levels of these agents will be higher in concentrates compared to isolates, due to the increased number of processing steps). It is in fact likely that Cruzat et al. (2014) are right, when they say that its the cocktail of amino acids, proteins, peptides and other micro- and macronutrients, vitamins and minerals in whey protein that acts via direct and indirect pathways (e.g. via optimizing the redox status / GSH) on the immune function of athletes.

Bottom line: While there is good evidence for vitamin D supplementation (1,000-2,000IU/day in individuals with low levels and / or hard-working athletes during the winter months) and high doses of glutamine in hard working athletes. There is little doubt that the amino acid + protein + peptide coctail in whey proteins is the "goto supplement" you would choose if you wanted to use only one of the supplements discussed in this article.

Whey Beyond Brawn: 10+ Things You Probably Didn't Know Whey & Peptides That Form During its Digestion Can Do | learn more.

In that, a reasonable dosage suggestion would be similar to that for maximal muscle hypetrophy and range from 20-60g per day - with the higher dosage being consumed in 2-3 servings evenly spread accross the day. Furthermore, studies like the one by Cury-Boaventura et al. (2008) indicate that, during periods of intense training, it may be useful to add glutamine. Either in large amounts of 10-20g per day (5-10g on top of each serving of whey) or, as it was the case in said study, as a dipeptide which has a higher chance of making it past the splachnic bed and not ending up as "fuel" for your organs and or glyconeogenic substrate in the liver.

And yes, if you've already caught a cold, 1 gram (in divided doses) of the the good old vitamin C (if you want to along with 5-15mg of zinc) is useful, as well - along with plenty of rest and sleep, of course ;-) Comment on Facebook!

References:

• Cury-Boaventura, Maria Fernanda, et al. "Effects of exercise on leukocyte death: prevention by hydrolyzed whey protein enriched with glutamine dipeptide." European journal of applied physiology 103.3 (2008): 289-294.
• Bergman, Peter, et al. "Vitamin D and respiratory tract infections: a systematic review and meta-analysis of randomized controlled trials." PloS one 8.6 (2013): e65835. 
• Castell, L. M., E. A. Newsholme, and J. R. Poortmans. "Does glutamine have a role in reducing infections in athletes?." European journal of applied physiology and occupational physiology 73.5 (1996a): 488-490.
• Castell, L. M., et al. "Some aspects of the acute phase response after a marathon race, and the effects of glutamine supplementation." European journal of applied physiology and occupational physiology 75.1 (1996b): 47-53.
• Castell, Linda M., and Eric A. Newsholme. "The effects of oral glutamine supplementation on athletes after prolonged, exhaustive exercise." Nutrition 13.7 (1997): 738-742. 
• Cruzat, Vinicius F., et al. "Amino acid supplementation and impact on immune function in the context of exercise." Journal of the International Society of Sports Nutrition 201.4 (2014): 11:61.
• Cury-Boaventura, Maria Fernanda, et al. "Effects of exercise on leukocyte death: prevention by hydrolyzed whey protein enriched with glutamine dipeptide." European journal of applied physiology 103.3 (2008): 289-294.
• Ha, Ewan, and Michael B. Zemel. "Functional properties of whey, whey components, and essential amino acids: mechanisms underlying health benefits for active people (review)." The Journal of nutritional biochemistry 14.5 (2003): 251-258.
• He, Cheng-Shiun, et al. "Influence of vitamin D status on respiratory infection incidence and immune function during 4 months of winter training in endurance sport athletes." Exerc Immunol Rev 19 (2013): 86-101. 
• Hiscock, Natalie, and Bente Klarlund Pedersen. "Exercise-induced immunodepression–plasma glutamine is not the link." Journal of Applied Physiology 93.3 (2002): 813-822. 
• Lands, L. C., V. L. Grey, and A. A. Smountas. "Effect of supplementation with a cysteine donor on muscular performance." Journal of Applied Physiology 87.4 (1999): 1381-1385.
• Krause, Mauricio S., et al. "L-arginine is essential for pancreatic β-cell functional integrity, metabolism and defense from inflammatory challenge." Journal of endocrinology 211.1 (2011): 87-97.
• Krause, Mauricio, et al. "Differential nitric oxide levels in the blood and skeletal muscle of type 2 diabetic subjects may be consequence of adiposity: a preliminary study." Metabolism 61.11 (2012): 1528-1537.
• Kreider, Richard B., et al. "Effects of ingesting protein with various forms of carbohydrate following resistance-exercise on substrate availability and markers of anabolism, catabolism, and immunity." Journal of the International Society of Sports Nutrition 4.1 (2007): 1-11.
• Maggini, S., S. Beveridge, and M. Suter. "A combination of high-dose vitamin C plus zinc for the common cold." Journal of International Medical Research 40.1 (2012): 28-42.
• Murdoch, David R., et al. "Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy AdultsThe VIDARIS Randomized Controlled TrialVitamin D3 and Upper Respiratory Tract Infections." Jama 308.13 (2012): 1333-1339.
• Newsholme, Philip, et al. "BJSM reviews: A to Z of nutritional supplements: dietary supplements, sports nutrition foods and ergogenic aids for health and performance—Part 18." British journal of sports medicine 45.3 (2011): 230-232.
• Nieman, David C., et al. "Vitamin E and immunity after the Kona triathlon world championship." Medicine and science in sports and exercise 36 (2004): 1328-1335.
• Nieman, David C., and Nicolette C. Bishop. "Nutritional strategies to counter stress to the immune system in athletes, with special reference to football." Journal of sports sciences 24.07 (2006): 763-772.
• Nieper, A. "Nutritional supplement practices in UK junior national track and field athletes." British journal of sports medicine 39.9 (2005): 645-649. 
• Pendergast, David R. "Effect of dietary intake on immune function in athletes." Sports medicine 32.5 (2002): 323-337.
• Schwarz, Eveline, et al. "Oral administration of freshly expressed juice of Echinacea purpurea herbs fail to stimulate the nonspecific immune response in healthy young men: results of a double-blind, placebo-controlled crossover study." Journal of Immunotherapy 25.5 (2002): 413-420.
• Waldron, Jenna Louise, et al. "Vitamin D: a negative acute phase reactant." Journal of clinical pathology (2013): jclinpath-2012. 
• Wernerman, Jan. "Clinical use of glutamine supplementation." The Journal of nutrition 138.10 (2008): 2040S-2044S.

Additional(!) HIIT Training Beneficial for Professional Judo Athletes: +15% Increases in Peak and Mean Power & Less Body Fat after 8-Week Training Camp.

Image 1: The Korean National Team - this are the kind of study subjects you want to look for if you are searching for studies that may help you, a fit physical culturist to improve your performance (img Yahoo)

Those of you who have been following the SuppVersity posts for quite some time now, know that I have continuously been ranting against classic endurance training. Not so much, because I think that this is not a sport you can enjoy (I know from personal experience that the "joy" can easily become addictive, though), but because many people perform what they think would be "healthy cardiovascular exercise" with the false expectation that running a marathon will improve their health and physique - more often, than not, the opposite is the case. And negative effects on both your physique (unless you consider being called a skeleton flattering) and longterm health become almost inevitable, when your daily 30 minutes of jogging or your 1h brief walk with your dog progressively increases to a frantic 10k run.

To each his own high intensity training

Image 2: Add 100-150lbs to a weight-west and test how "low" the intensity of a 4km/h walk on a treadmill is for the morbidly obese subjects in the studies that perpetuate the myth of the fat-burning effects "low intensity" exercise (img rosstraining.com).

And while the medical orthodoxy keeps putting out review after review emphasizing how beneficial classic endurance exercise is for the obese prediabetic, they do not give a damn that the 4km/h walk on a treadmill that makes the 250pound sedentary housewife sweat, pant and lose weight, will not have any impact on the girl with the unsexy love-handles who finally wants to get the body of the Shape cover models she is admiring. I mean, think about it: It's all about intensity! If the girl with the love-handles grabbed one of those military backpacks and loaded it with 5x30lbs plates, hopped on the treadmill and started walking at 4km/h, what would you call that? I would call it High Intensity Training (HIT). Now, the girl would probably fall off the treadmill every 30s because the load was way to heavy. What would you call it if she jumped back on after catching her breath? I would call it High Intensity Interval Training (HIIT). 

Assuming that you got the message, it should stand out of question that you as a reasonably fit physical culturist can adopt short (max. 50min) bouts of low intensity endurance training as a means of regeneration, but if you are looking to improve your physique or exercise performance (outside of long-distance running) you are way better of if you follow the example of the 29 judoists from the Yongin University in Korea who participated in an 8-week study at the Korea National Sport University in Seoul (Lee. 2011).

Figure 1: Subject characteristics (left) and training program (right) of the 29 judoist participating in study (Lee. 2011)

If you take a look at the subject characteristics in figure 1 (left), you may note that this is the kind of study you and I must rely on, when we are designing our training routines if we want to improve our cardiovascular fitness level and shed the last unaesthetic pounds of body fat - and, if the results from this study translate into your training practice, the addition of an early morning HIIT sprinting session on Monday, Tuesday, Thursday and Friday (exact protocol cf. figure 1, right) could provide exactly that: a drop in body-fat and an increase in anaerobic performance. This is particularly noteworthy, because the subjects performed the interval training as part of an already arduous 8-week training camp with concurrent strength and judo training (I wonder if any of the participants was afraid to lose muscle ;-)

Figure 2: Effects of standard and standard + additional HIIT training on VO2Max, peak and mean power (left), as well as body composition in 29 judoists during an 8-week training camp (Lee. 2011)

With their already low body fat percentage of ~13% and a caloric intake of 3.500kcal/day (remember none of the athletes wanted to lose weight), the slight (and statistically non-significant), yet nonetheless evident body-recompositioning effect is certainly not to be scoffed at, if you look at the profound performance increases in the anaerobic peak and mean power test (cf. figure 2).

That the VO2Max, i.e. the aerobic performance did not benefit above the normal protocol is yet an oddity of the study, (cf. "HIIT Even For Infarction Patients") of which the scientists assume that it could be related to the fact that the normal training protocol alone would have been enough to max out on the already high aerobic capacity of the athletes. Which, and thusly we have again come full circle, leads me back to my initial recommendation to fine-tune your training protocol to your needs, which (I would hope) are completely different from the ones of the average sedentary, obese, pre-diabetic resident of the Western hemisphere. And in case you want to learn more about how to do that, I suggest you come back tomorrow, for the next installment of the Intermittent Thoughts with tipps on programming success that will work regardless of whether you will or won't use an intermittent fasting protocol ;-)

Pre-Workout Nutrition & Supplementation for Athletes - What Works, What Doesn't Work | Perfect Timing, Fast or Slow Carbs, Glucose & Fructose, Fats, Protein & More

For sedentary, video-game and smartphone addicted youths, it's they're the gateway drug.. ah, I mean drink to insulin therapy for full-blown diabetes. For athletes CHO + caffeine containing drinks can be very useful.

As Michael J. Ormsbee and his colleagues point out in their latest review, "[e]ndurance athletes rarely compete in the fasted state, as this may compromise fuel stores." The means by which means endurance athletes (and anyone who is about to embark on a long(er) workout) should (pre-)fuel their workouts is yet still debated.

Some swear by whole foods, others stick to special carbohydrate mixes, others again combine carbohydrates and protein and many simply grab the next best energy drink or supplement with an allegedly "science-based" formula. What is optimal, however, isn't just determined by the amount of energy it delivers. It's also influenced by the metabolic effects of the preworkout meal.

Learn more about carbohydrates at the SuppVersity!

Intra-Workout CHO 101

Spit or Swallow Your Carbs?

Peri-Workout Supp Update

PWO CHO or PRO Supplementation?

194 Bananas in 3 Weeks - Healthy!

The Fructose Scam: An Update!

Having a ton of fat, but no carbohydrates, for example, could steer an athletes metabolism away from carbohydrate and toward fat metabolism. For a sprinter this would be a disaster, for an endurance athlete, on the other hand, it could have certain benefits.

When I look at the tabular overview of the studies, Ormsbee et al. reviewed in their latest paper, there is yet another factor that appears to have an even greater impact on the benefits of pre-workout meals / supplementation and that's timing! In the discussion of their results, the South African researchers write.

Figure 1: Drop in glucose in well-trained cyclist on the onset of 30min cycling exercise after ingestion of 75g glucose or fructose or placebo (Koivisto. 1981)

"The timing of CHO intake influences its metabolic effects. Indeed, insulin and blood glucose elevations are positively correlated with CHO meal proximity to exercise (Moseley. 2003). Studies in which CHO is consumed 1–4 h prior to exercise often report glucose and insulin levels declining to near-basal levels prior to exercise (Coyle. 1985; Kotsiopoulou. 2002; Chen. 2009).

Alternatively, when subjects consume CHO ≤60 min before exercise, insulin and blood glucose levels are reported to be elevated immediately prior to exercise (Koivisto. 1981; Chryssanthopoulos. 1994; Febbraio. 2000a,b)." (Ormsbee. 2014)

What both the 1-4h prior and the <60 min pre-exercise approach have in common is that they trigger an initial drop in blood glucose at the onset of the exercise period. Interestingly, the latter is more pronounced for shorter time-spans between the ingestion of the meal / nutrient supplement and the workout.

If we go by the general trend in the studies,Ormsbee et al. reviewed, it appears as if you'd better leave 60min between your last meal and your workout if you want to benefit.

Take home message T as in "timing": If you belong to the unfortunate few percent of people who bunk at the beginning of their workouts don't eat in the 1h-pre time.window. Other ways to at least reduce the drop in blood glucose are: (1) use fruits / fructose instead of glucose and (2) skip the pre-workout meal altogether ;-)

In general, it's not necessary to consume "slow" carbs. Chen et al. for example observed performance increases with high, but not with low GI carbs ingested 2h before a workout (Chen. 2009); what Ormsbee et al. don't mention in their overview, tough, is that this worked only, because the subjects supplemented 2h before and during the workout.

In view of the aforementioned problem with reductions in blood glucose it should be obvious that consuming high glycemic index (high GI) carbohydrates before a race may not be ideal.

Figure 2: When they are ingested 30 min before an endurance exercise bouts, slow digesting carbohydrates (LGI) from muesli have no advantage over fast digesting carbs (HGI) from instant mashed potatoes [please not that this study also shows that it doesn't have to be Gatorade or other sugar water]; on the contrary, the lactate levels after the workout were lower and the total work was higher (albeit not significantly) in the HGI trial (Febbraio. 2000a)

The experimental evidence, on the other hand, shows that when the high GI meal (instant mashed potatoes) is consumed 30 minutes before the workout, there are no negative effects on the exercise performance of 8 trained men who cycled at 70% peak oxygen uptake for 120 min followed by a 30-min performance cycle (see Figure 2).

Fat burning machines train low and compete high!?

Similarly, the evidence for the usefulness of high fat feeding immediately before a competition isn't there (Ormsbee. 2014). Rather than that many endurance athletes who follow a lowe(er) carbohydrate diet, "train low" and "compete high" - in this case "high" and "low" don't refer to the altitude, thought, but indicate training with a low carbohydrate intake and increasing the carbohydrate intake shortly before a competition. Some experts see this critically, though. Louise M. Burke, for example, writes:

"More recently, it has been suggested that athletes should train with low carbohydrate stores but restore fuel availability for competition (‘‘train low, compete high’’), based on observations that the intracellular signaling pathways underpinning adaptations to training are enhanced when exercise is undertaken with low glycogen stores. The present literature is limited to studies of ‘‘twice a day’’ training (low glycogen for the second session) or withholding carbohydrate intake during training sessions. Despite increasing the muscle adaptive response and reducing the reliance on carbohydrate utilization during exercise, there is no clear evidence that these strategies enhance exercise performance. Further studies on dietary periodization strategies, especially those mimicking real-life athletic practices, are needed." (Burke. 2010; my emphasis)

In an article in the Journal of Sports Sciences Burke wrote with John A. Hawley, Stephen H. S. Wong & Asker E. Jeukendrup, the authors accordingly classify the "train low, compete high"-principle as principle with "equivocal evidence" (Burke. 2011).

But what about fat adapation and keto-athletes? Obviously Burke's position stands in contrast to papers by Volek, Noakes and Phinney who have recently repeated their conviction that "the shift to fatty acids and ketones as primary fuels when dietary carbohydrate is restricted could be of benefit for some athletes" (Volek. 2014), even though they still cannot provide the scientific evidence that would turn the "could" in the previously cited sentence into a "can".

More recent research again suggests that we may not even be dealing with an "either or" problem, here. In fact, an experiment Murakamiet al. conducted only recently would suggest:

Could using fat and carbs, instead of fat or carbs increase performance even more?

The scientist from the Fukuoka University examined the performance effect of consuming either: (1) a high-fat meal 4 h pre-exercise + a placebo jelly 3 min before exercise (HFM + P); (2) a high-fat meal 4 h pre-exercise + maltodextrin jelly 3 min before exercise (HFM+ M); or (3) a high-CHO meal 4 h pre-exercise + placebo jelly 3 min before exercise (HCM + P).

The study was conducted after the subjects, eight  male collegiate long-distance athletes, who engaged in physical training almost every day, had consumed an isocaloric, high-CHO diet for three days (2562 ± 19 kcal). The isocaloric test meals (1007 ± 21 kcal) were consumed 4 h before a standardized exercise test consisting of 80 min submaximal runing on a treadmill at each runner’s pre-determined lactate threshold (LT) speed.

Post-workout muscle glycogen resynthesis with glucose or glucose + fructose (Casey. 2000)

What's the right starch for you? Unless you plan to work out for less than 20 minutes, you should prefer slow digesting modified starches (resistant starches) like WM-HDP over fast-digesting ones like Vitargo(R) in your pre-workout nutrition. When it comes to intra-workout nutrition, though, A mix of both fast and slow digesting carbs can yield additional benefits. The same holds true for post-workout supplementation, where the isocaloric replacement of up to 50% of the glucose with fructose can make the tons of sugar easier to handle for your stomach (Casey. 2000), and the addition of 0.4g/kg of fast digesting protein to 0.8g/kg carbohydrates can significantly increase the glycogen resynthesis after workouts (van Loon. 2000).

The endurance component was immediately followed by a time trial to exhaustion (TTE), where the HFM + M group were able to run 8% (8 minutes) longer than their peers in the HFM + P  and the 10% longer than the HCM + P group. As Ormsbee et al. highlight in their review:

"This suggests that CHO feeding subsequent to a HFM pre-exercise and three days of a proper CHO loading protocol can elicit an enhancement in the endurance performance of well-trained runners.[...] however, Murakami and colleagues did not include a HCM + M group, which raises questions about whether the HFM + M group performed longer primarily due to HFM [i.e. due to the extra fat] or rather as a result of the increased caloric consumption of maltodextrin immediately pre-exercise." (Ormsbee. 2014)

It appears likely that this methodological issue renders the study results more or less worthless, because previous studies have found more or less unequivocally that fat and fat & carbohydrate supplements don't increase the exercise performance of endurance athletes:

• 

  Figure 3: Next to changes in substrate oxidation (CHO ￬ | FAT ￪) the blunted growth hormone response was the only sign. difference Whitley et al. found when they compared a high carbohydrate to a high fat meal (Whitley. 1998)

  Whitley et al. (1998) who couldn't find a performance increase w/ 50g of carbohydrates, 14g protein and 80g fat during 90 min cycling 70% VO2max and a 10 km TT
• Okano, G., et al. (1996) who didn't find performance increases in response to the ingestion of a 30% carbohydrate, 61% fat and 9% protein meal 4h before an exercise test that consisted of cycling at 65% of the maximal oxygen consumption for the first 120 min of exercise, followed by an increased dose of 80 % V0_max,
• Rowlands et al. (2002) who found no benefits of consuming a high fat meal before a 50-km time trial, and
• Paul, et al. (2003) who found that even dosed at 1.3g/kg body weight a high fat meal has no effect on timetrial performance of 8 trained men.

Overall, the combination of fat and carbohydrates or the use of fat instead of carbohydrates does therefore appear similarly futile. What is important, though, is that having fats in your preworkout meal is not going to decrease your workout performance significantly. Moreover, it remains to be seen, whether the results differ in "fat adapted" athletes in future studies.

Caffeine & protein, the bodybuilder's darlings

Both caffeine and protein have been shown to be useful for endurance athletes, but only the former, i.e. caffeine supplements will lead to significant performance increases.

"Regardless of an athlete’s genetic disposition, a dose of 3–6 mg of caffeine/kg of body weight has been shown to enhance performance in most individuals, with no further benefit from higher doses." (Ormsbee. 2014)

For the latter, i.e. protein, the latest review clearly states that the contemporary evidence shows that

"[...] when carbohydrate supplementation was delivered at optimal rates during or after exercise, protein supplements provided no further ergogenic effect, regardless of the performance metric used." (McLellan. 2014)

What protein supplements can do, though, is to speed up the glycogen resynthesis and glycogen hypersaturation after workouts (Morifuji. 20045) and contribute and "enhance skeletal muscle remodelling and stimulate adaptations that promote an endurance phenotype" (Moore. 2014).

 Post-Workout Glycogen Repletion - The Role of Protein, Leucine, Phenylalanine and Insulin. Plus: Protein & Carbs How Much do You Actually Need After a Workout? Learn more about PWO supplements

Bottom line: Last week I've concluded that there is currently no alternative to carbohydrates, when it comes to intra-workout supplementation on long(er) duration endurance races. This week, the conclusion I will borrow from Ormsbee et al is not much different: "Consuming a CHO-rich meal [>0.8g/kg body weight] in the hours prior to endurance exercise appears to benefit performance."

The use of high fat supplements or additional fat in a pre-workout meal, on the other hand has no significant scientific backup that would suggest that it does anything, but shift the substrate metabolism from high glucose to medium glucose & medium fat oxidation. Protein and caffeine, on the other hand can help. Yet only caffeine (0.3-0.6mg/kg) is something that will have immediate performance enhancing effects, when it's consumed before a workout. Protein, on the other hand, should be consumed in the post-workout phase instead  | Comment on Facebook!

Ah, and yes: (A) You can use bananas, mashed potatoes and other whole foods instead of sugar drinks. And (B) These suggestions are also valid for strength trainees, who like their workouts (1) intense, (2) long (>35 minutes) and (3) with only 60s of rest between sets. If you are one of the "let's take a break" guys who spends 2h in the gym doing ten sets of bench presses and a lot of talking, you better spare yourself the carbohydrate load before the workout.

References:

• Burke, L. M. "Fueling strategies to optimize performance: training high or training low?." Scandinavian journal of medicine & science in sports 20.s2 (2010): 48-58.
• Burke, Louise M., et al. "Carbohydrates for training and competition." Journal of Sports Sciences 29.sup1 (2011): S17-S27.
• Casey, Anna, et al. "Effect of carbohydrate ingestion on glycogen resynthesis in human liver and skeletal muscle, measured by 13C MRS." American Journal of Physiology-Endocrinology And Metabolism 278.1 (2000): E65-E75.
• Chen, Y. J., et al. "Effects of glycemic index meal and CHO-electrolyte drink on cytokine response and run performance in endurance athletes." Journal of Science and Medicine in Sport 12.6 (2009): 697-703. 
• Coyle, Edward F., et al. "Substrate usage during prolonged exercise following a preexercise meal." J Appl Physiol 59.2 (1985): 429-33.
• Chryssanthopoulos, C., L. C. Hennessy, and C. Williams. "The influence of pre-exercise glucose ingestion on endurance running capacity." British journal of sports medicine 28.2 (1994): 105-109.
• Febbraio, Mark A., et al. "Effects of carbohydrate ingestion before and during exercise on glucose kinetics and performance." Journal of Applied Physiology 89.6 (2000a): 2220-2226.
• Febbraio, Mark A., et al. "Preexercise carbohydrate ingestion, glucose kinetics, and muscle glycogen use: effect of the glycemic index." Journal of Applied Physiology 89.5 (2000b): 1845-1851.
• Kotsiopoulou, Christina, and Veronica Vleck. "The effect of a high carbohydrate meal on endurance running capacity." International journal of sport nutrition and exercise metabolism 12 (2002): 157-171.
• Koivisto, Veikko A., Sirkka-Lisa Karonen, and Esko A. Nikkila. "Carbohydrate ingestion before exercise: comparison of glucose, fructose, and sweet placebo." J Appl Physiol 51.4 (1981): 783-787. 
• McLellan, Tom M., Stefan M. Pasiakos, and Harris R. Lieberman. "Effects of Protein in Combination with Carbohydrate Supplements on Acute or Repeat Endurance Exercise Performance: A Systematic Review." Sports Medicine 44.4 (2014): 535-550.
• Moseley, Luke, Graeme I. Lancaster, and Asker E. Jeukendrup. "Effects of timing of pre-exercise ingestion of carbohydrate on subsequent metabolism and cycling performance." European journal of applied physiology 88.4-5 (2003): 453-458.
• Moore, Daniel R., et al. "Beyond muscle hypertrophy: why dietary protein is important for endurance athletes 1." Applied Physiology, Nutrition, and Metabolism 39.999 (2014): 1-11.
• Morifuji, Masashi, et al. "Dietary whey protein increases liver and skeletal muscle glycogen levels in exercise-trained rats." British journal of nutrition 93.04 (2005): 439-445.
• Murakami, Ikuma, et al. "Significant effect of a pre-exercise high-fat meal after a 3-day high-carbohydrate diet on endurance performance." Nutrients 4.7 (2012): 625-637.
• Okano, G., et al. "Effect of 4h preexercise high carbohydrate and high fat meal ingestion on endurance performance and metabolism." International journal of sports medicine 17.07 (1996): 530-534.
• Ormsbee, Michael J., Christopher W. Bach, and Daniel A. Baur. "Pre-Exercise Nutrition: The Role of Macronutrients, Modified Starches and Supplements on Metabolism and Endurance Performance." Nutrients 6.5 (2014): 1782-1808.
• Paul, David, et al. "No effect of pre-exercise meal on substrate metabolism and time trial performance during intense endurance exercise." International journal of sport nutrition and exercise metabolism 13 (2003): 489-503.
• Rowlands, David S., and Will G. Hopkins. "Effect of high-fat, high-carbohydrate, and high-protein meals on metabolism and performance during endurance cycling." International journal of sport nutrition and exercise metabolism 12 (2002): 318-335.
• van Loon, Luc JC, et al. "Maximizing postexercise muscle glycogen synthesis: carbohydrate supplementation and the application of amino acid or protein hydrolysate mixtures." The American journal of clinical nutrition 72.1 (2000): 106-111.
• Volek, Jeff S., Timothy Noakes, and Stephen D. Phinney. "Rethinking fat as a fuel for endurance exercise." European journal of sport science ahead-of-print (2014): 1-8. 
• Whitley, Helena A., et al. "Metabolic and performance responses during endurance exercise after high-fat and high-carbohydrate meals." Journal of Applied Physiology 85.2 (1998): 418-424.

Beta-Alanine Does not Make it From Bench to Pool Side: Are the Effects Too Short-Lived? Is Swimming the Wrong Sport? Or Was the Dosage of 3.2g/day Simply Too Low?

Michael Phelbs holding his record-setting 19th Olympic medal. According to the results of the latest Australian study on the real-world effects of beta alanine supplementation during the training and competitive season in elite national level swimmers the touted ergogenic is unlikely to have helped him win only one of those.

As the headline of today's SuppVersity post already suggests, a recently published paper by scienstists from the Australian Institute of Sport, the Institute of Sport, Exercise and Active Living (ISEAL), and the Queensland Sport and Athletics Centre (QSAC) does unfortunately raise about as many new questions about the real-world value of beta-alanine supplementation as it answers. And that despite the fact that the researchers originally set out to bridge the existing gap between the existing research on beta-alanine supplementation, which involves mainly non-elite participants and laboratory-based performance tests, which do not necessarily relate to elite level sport, on the one hand, and the real world effects of beta-alanine "supplementation in elite athletes on training and competition in a real-world setting" (Chung. 2012), on the other hand.

Beta alanine doesn't make it from bench to pool edge...

In the course of the 10-week study the researchers measured the exercise performance, as well as lactate levels, blood pH and bicarbonate levels of the 60 (34 male and 26 female)elite/sub-elite swimmers they had convinced to take part in the study after they had taken part in standardized tests, which were designed to to tailor to the athletes' individual race distances...

Figure 1: Schematic timeline of study design (Chung. 2012)

• Sprint: 4 × 50-m on a 3 min cycle (maximal) + 100-m maximal effort 
• Middle distance: 6 × 50-m on a 2 min cycle (maximal) + 200-m maximal effort 
• Distance: 8 × 50-m on a 1.5 min cycle (maximal) + 200-m maximal effort 

...at the beginning, after 4 weeks and at the end of the study (week 10). With the exception of the testing days, the athletes followed their own training and competition schedule while supplemented with

• 4.8 g per day (two 800 mg tablets, three times daily) of beta-alanine or placebo with meals in the initial 4-week loading phase and
• 3.2 g/day (two tablets, twice daily) of beta-alanine or placebo for the remainder of the study period (6-week maintenance phase). 

Needless to say that all supplements, regardless of whether they contained the active sustained release beta-alanine from Musashi (Australia) or the maltodextrin placebo from GMP Pharmaceuticals, looked absolutely identical.

Were the results skewed due to the insufficient blinding of the study? No, "the beta-alanine supplemented swimmers who correctly guessed their treatment did not perform better that those who believed they were on placebo." (Chung. 2012)

Yet despite these precautions and the use of porportedly tingling free sustained preparations 10 out of 12 respondents in the BA group (total participant in this group n=22) who correctly guessed the identity of the supplement they received reported mild paraesthesia. In the placebo group on the other hand, "12 out of 19 respondents guessed correctly, attributing it to the absence of side effects (5 respondents) and taste (3 respondents)." (Chung. 2012)

And that did not work at all?

When the title of this post says that "beta-alanine does not make it from bench to pool side", this is actually not quite correct. With a reference value of 0.3% for the smallest worthwhile change used to compare the competition performance and an outcome measure being deemed unclear when the confidence interval crossed limits for both a substantially positive and negative effect, the statistical analysis of the data of the 43 swimmers that did not drop out due to injuries or simply lost interest in the study at one point or another, showed that

"[t]here was an unclear effect (0.4%; ±0.8%, mean, ±90% confidence limits) of beta-alanine on competition performance compared to placebo with no meaningful changes in blood chemistry, as well as an unclear effect at ten weeks (−0.2%; ±1.5%) and no meaningful changes in blood chemistry." (Chung. 2012)

It is therefore hard to debate the researcher's conclusion that contrary to the results observed in artificial laboratory settings, "[b]eta-alanine supplementation appears to have minimal effect on swimming performance in non-laboratory controlled real-world training and competition settings." (my emphasis; Chung. 2012)

Couldn't it be that 4 weeks and/or 4.8g instead of 3.2g the magic numbers?

Whether this "failure" is only a result of the "non.laboratory controlled real.world training and competition setting", appears yet questionable. After all, the data in figure 2 goes to show you that there are "small difference" in lactate concentrations, specifically in week 4:

Figure 2: Blood ph and bicarbonate concentrations after the standardized exercise tests in week 0, week 4 and week 10 expressed relative pre-test values (left) and corresponding lactate concentration (right) expressed relative to average in all trial (11.6 mmol/l; data adapted from Chung. 2012)

And while lower lactate levels are usually indicative of lower exercise performance due to lower buffering (and thus higher lactic acid production), the higher intra-cellular buffer capacity due to  the beta-alanine induced increases in carnosine stores, did yield even smaller, but measurable perfomance increases in the corresponding tests in week 4, when the race perfomance times transiently improved by −1.3% in the beta alanine group.

Based on the latter observation, we can negate the second of the three questions in the headline, because if we assume that these performance increases, as transient as they may have been were real, this means that swimmers can benefit from beta-alanine supplementation - even if the benefit is marginal. We are now however still left with the first and second question from the headline, I want to briefly address before we go on to the implications and conclusion of today's blogpost.

Figure 3: Muscle carnosine levels in bodybuilders and untrained controls (data based on Tallon. 2005)

1. Are the effects of beta alanine only short lived and chronic supplementation useless? This hypothesis would actually be somewhat supported by the results of Hill et al. who found that the total work done during a cycling capacity test increased by 13% over placebo after 4 weeks but kept increasing only 3.2% in the remaining 6 weeks, before the study ended (Hill. 2007). This is clear cut evidence for the non-linear and certainly not accumulative nature of the ergogenic effects of beta-alanine (and a vast amount of other processes in nature, by the way, linearity is more or less the exception from the rule, so to say ;-)
   
   Moreover these effect were observed in recreationally active men, in whom the effects of beta-alanine supplemetation are probably lower to begin with, we could speculate that this "diminishing returns effect", as you may call it, would be even more pronounced in trained athletes. After all, especially those, in whom muscle carnosine levels actually matter, i.e. sprinters, weight lifters and, as the data in figure 3 goes to show,  bodydbuilders do already have much higher muscle carnosine concentrations than age-matched untrained subjects (in the absence of supplementation, of course!).
    
2. Do you need a higher dosage than just 3.2g/day if you are an athlete athlete? 15 out of 18 studies in Hobson et al. 2012 meta-review used doses between 4.0 - 6.0g/day (Hobson. 2012). In only four of those studies the subjects were anywhere near "professional" athletes. As mentioned before strength athletes, sprinters and everyone else who would be particularly prone to benefit from beta alanine tends to have already higher intramuscular carnosine levels (cf. figure 3). Against that background, it appears only reasonable to assume that elite athletes would require higher doses of beta-alanine than rookies or non-trained individuals to increase their intramuscular carnosine stores (which is the whole point in supplementing with beta-alanine) even further. On the other hand, it is likewise possible that a further increase simply won't take place or is too small, irrespective of the dose to result in real world performance increases.

And if neither of those two hypothesis holds, it may still all come down to the outcome measures researcher use to gauge the effects. In this regards, Chung et al. rightfully state that their results are actually in accordance with the most recent meta-analysis by Hobson and colleagues (Hobson. 2012), who discussed divergent research findings from studies utilizing “capacity” and “performance” type protocols.

"Hobson and colleagues found that beta-alanine supplementation had a moderate effect on exercise capacity while having no benefit on measures of exercise performance due to the employment of pacing strategies." (Chung. 2012).

Conversely, Chung et al. saw minimal improvements in the high-intensity training “capacity” sets of their standardized testing protocol (the 4-8x 50m sprints), yet not in the far more imporant “performance” measure, i.e. competition component of their investigation.

Figure 4: With a carnosine washout time of at least 9 weeks (in "low responders") there is no reason to take BA chronically (data shows skeletal muscle carnosine in healthy untrained men relative to baseline at week T=-5/-6 after 5-6 weeks of 4.8 g/day β-alanine supplementation; based on Baguet. 2009)

Bottom line: Overall the results of the study at hand do therefore not confute the use of beta alanine as an ergogenic aid, per se. They should however make you reconsider, whether the simple addition of the suggested 3.2g/day of beta-alanine to an at least for some of you already borderline excessive supplement regimen is really necessary and whether shorter, yet maybe higher dose cyclic supplementation at time points, where you are most likely to benefit from the 1-2% performance gain in training capacity (e.g. phases of planned over-reaching, the high volume phase of a macrocycle, etc.) would not be a more prudent way to use beta-alanine. After all, the data in figure 4, though once again from untrained individuals, shows that it takes roughly 9 weeks even in the "low responders" for the increase in skeletal muscle carnosine to be reversed again.

There is no need to take it religiously day in day out, then, because there is as of yet no evidence that a couple of workouts would decrease the tissue level of carnosine, again.In fact, the naturally increased carnosine levels in athletes (see figure 3) would rather suggest that the exact opposite is the case, i.e. that exercise in the presence of an adequate nutrient supply would increase the carnosine buffer of your muscles, anyway.


References:

• Baguet A, Reyngoudt H, Pottier A, Everaert I, Callens S, Achten E, Derave W. Carnosine loading and washout in human skeletal muscles. J Appl Physiol. 2009 Mar;106(3):837-42. 
• Chung W, Shaw G, Anderson ME, Pyne DB, Saunders PU, Bishop DJ, Burke LM. Effect of 10 Week Beta-Alanine Supplementation on Competition and Training Performance in Elite Swimmer. Nutrients. 2012; 4:1441-1453.
• Hill CA, Harris RC, Kim HJ, Harris BD, Sale C, Boobis LH, Kim CK, Wise JA. Influence of beta-alanine supplementation on skeletal muscle carnosine concentrations and high intensity cycling capacity. Amino Acids. 2007 Feb;32(2):225-33.
• Hobson, R.; Saunders, B.; Ball, G.; Harris, R.; Sale, C. Effects of β-alanine supplementation on exercise performance: A meta-analysis. Amino Acids 2012, 43, 25–37.
• Tallon MJ, Harris RC, Boobis LH, Fallowfield JL, Wise JA. The carnosine content of vastus lateralis is elevated in resistance-trained bodybuilders. J Strength Cond Res. 2005 Nov;19(4):725-9. PubMed PMID: 16287364.

Amino Acids for Super Humans, Part IV - Purported Ergogenics (3/3): Glutamine, the Anabolic Immune Booster?

Image 1: Still one of the top-
sellers in almost all supplement
shops - l-glutamine; tip: buying
bulk powder will save money

Although glutamine is one of the non-essential amino acids, even the fact that your body continuously 'sacrifices' truly essential amino acids to synthesize glutamine in your muscle tissue, should go to tell you that, after all, glutamine, the most abundant amino acid in human muscle and plasma, cannot be so non-essential as its classification would suggest.

Under normal conditions it forms 50% of the whole body amino acid pool. In cells, esp. muscles, where glutamine makes up 66% of the amino acid pool. Within the cellular space, the purported cell-volumizer can reach concentrations that are up to 33 times higher than on the outside of the cell.

In times of acute stress, severe burns or surgical trauma, on the other hand, tissue glutamine levels have been observed to decline by up to -50% - an observation, which gave and still gives rise to the hypothesis that glutamine repletion / supplementation could ameliorate or even prevent the catabolic processes which threaten all metabolically active tissues and weaken the immune system whenever the human body is exposed to severe physiological (and even psychological) stress. In that, it is important to understand that glutamine does not reduce the amount of corticosteroids which are released in those circumstances, but may reduce the negative effects of increased cortisol and catecholamine levels on the body. In a 1995 study by Hickson et al., for example, intravenous infusion of glutamine reduced muscle mass losses subjects who had previously received a glucocorticoid infusion by -70% and ameliorated the cortisol-induced decline in untra-muscular myosin heavy-chain content by -50% (Hickson. 1995). 

Did you know that 90% of the nitrogen that is derived from BCAA catabolism is released as glutamine, which is formed primarily in your muscles, but also in your lungs, your liver and your brain in a process called glutamine synthase, where glutamate, which has a side-chain hydroxyl instead of the amine group of glutamine, and ammonia are synthesized to form glutamine. During its subsequent hydrolysis, i.e. the catalysis of glutamine to glutamate + ammonia in the intestine, cells of the immune system and the liver, a substantial amount of energy is released. In that, glutamine, the 2nd major interorgan nitrogen carrier, derives a major advantage over alanine, the #1 interorgan nitrogen carrier, from its protein and amino acid derived carbon skeleton, which constitutes an energetically denser substrate for gluconeogensis (esp. in the liver) than that of alanine or aspartate, the third most abundant interorgan nitrogen carrier in the human body.

Note: This is the detailed transcript of my show notes to "Amino Acids for Super Humans Part IV"
click here to download the podcast if you want to listen before / during / after you read the rest of the notes

I. Physiological role of glutamine in the human body

Stress-protection aside, glutamine performs a whole host of other important physiological functions. Glutamine...

• ... is required for hepatic ureagenesis and renal ammoniagenesis, is an essential contributor to detoxification processes;
• ... is necessary to maintain and restore an optimal ph-balance;
• ... is a substrate / precursor to peptides and proteins, amino sugars, purines and pyrimidines;
• ... is used as cellular fuel in muscle, intestine, skin and immune system, where it's availability / non-availability directly regulates protein synthesis and degradation;
• ... is intricately involved in the anti-oxidant defense system of the body as a precursor to glutathione (=glutamate + cysteine + glycine) production.

Glutamine and intestinal health & function

You may be surprised to see that I devote an entire chapter of this write-up to the role of glutamine in gut health; yet with the increasing public interest in and scientific awareness of pathologies beyond Crohn's, Celiac & Co, I consider the direct effects glutamine and glutamic acid exert on the health of the intestinal system of paramount importance.

Table 1: Effects of glutamine supple-
mentation on intestinal health
(Stehle & Fürst in ed. Cynober. 1955)

In their contribution to Pharmacological nutrition: immune nutrition (ed. Cynober, Fürst, Lawin. 1995) Stehle and Fürst compiled a list of immediate effects of glutamine supplementation on gut function (cf. table 1), many of which could be of great importance for athletes, who are not only particular reliant on optimal nutrient absorption, but also at an extraordinary risk of developing increased gut permeability, which has lately become commonly known and almost hysterically feared as "leaky gut" (syndrome). In this context, Carl V. Gisolfi writes in a review of the importance of optimal intestinal function for athletes (Gisolfi. 2000):

An increase in gut permeability may be an important link to gut-barrier impairment (Fig. 3). The hypothesis proposes that exercise stress produces biochemical changes that uncouple oxidative phosphorylation, reducing ATP produc ion and increasing Ca2+ efflux from mitochondria and endoplasmic reticulum. These events lead to increased cytosolic Ca2+ concentration, the generation of reactive oxygen species, and loss of tight junction control, producing increased intestinal permeability. [...] When the tight junctions open, their maxi-
mal channel size is too small to permit passage of endotoxin but will allow passage of luminal contents that are chemotactic for neutrophils. These agents (dietary antigens, chemotactic oligopeptides) stimulate intraepithelial lymphocytes to secrete interferon-γ. [...] Interferon-γ opens tight junctions and activates macrophages and neutrophils to release oxygen radicals and immunosuppressive peptides. Thus increasing intestinal permeability by opening tight junctions can initiate immunologic and inflammatory events that can alter gut structure and function.

Image 2: More than 50% of the
dietary glutamine are used by your
digestive system and do not even
reach systemic circulation.

Scientifically documented causative factors for increased gut permeability in athletes are ...

• prolonged exercise (triathlon, marathon, etc.)
• high intensity endurance exercise at 80% of VO2 max
• (co-)ingestion of aspirin with medium intensity exercise at 60-65% of VO2 max

And desite the fact that Coeffier et al., in a recent review on the efficiacy of gutamine supplementation in patients with irritable bowel syndrome, state that previous "clinical studies with oral glutamine in CD [Crohn's disease] are until now disappointing" (Coeffier. 2010). There is substantial evidence for glutamine to exert beneficial effects on overall enterocyte health and accumulating evidence for the ability of glutamates, the carboxylate anions and salts of glutamic acid, to stabilize the gut lining and to reduce intestinal permeability (Vermeulen. 2011).

Did you know that in a 2010 study by dos Santos et al. (dos Santos. 2010), administration of glutamine at a dose of 500mg/kg/day (human equivalent ~40mg/kg or 3.2g per day for an adult weighing 80kg) to mice with experimentally induced intestinal obstruction "decreased intestinal permeability and bacterial translocation to physiologic levels in the treated animals and preserved intestinal barrier integrity".

Thus, even if the following dissertations will entail the conclusion that the ergogenic value of glutamine is largely overrated, the increase in gut permeability that has been observed after strenuous workouts (Davis. 2005) would be an argument in favor of post-workout glutamine / glutamic acid supplementation, you should remember.

II. Glutamine and the athlete

While intravenous glutamine infusions are a longstanding and well-established part of medical treatment strategies used in hospitalized and critically ill patients (Windle. 2006), the use(-fulness) of glutamine as a dietary supplement for athletes is still questioned by many of the practicing exercise and nutrition scientists. In the following I will try to tackle the two most frequent promises you ill hear and read about in the advertisements for respective products.

"Glutamine supplementation saves athletes from getting sick"

It is unquestionably true that glutamine is of paramount importance for healthy immune function (Calder. 1999).
It is also non-debatable that intense exercise, and, in that, specifically chronic endurance exercise (cf. figure 1),  has been shown to decrease both serum as well as tissue glutamine levels.

Figure 1: Serum glutamine and glutamate levels in ultra-marathon runners pre- and at different time-points post exercise (data adapted from Castell. 1997)

As the data from figure 1 documents, the exercise induced decline of glutamine levels is yet far from being as dramatic as the -50% drop which has been reported for hospitalized critically ill patients. Nevertheless, the highly advertisable claims of increased incidences of upper respiratory infects due to weakened immunity secondary to exercise induced glutamine-deficiency are going on forever and I doubt that this will ever change, although the recently published position stand on dietary supplements by Walsh et al. is only the latesst in a line of reviews to conclude, based on contemporarily available evidence, that glutamine supplementation for athletes is "[n]ot recommended, [because] body stores [generally] exceed exercise-lowering effects" (Walsh. 2011).

With reference to the purported beneficial effects of supplemental glutamine on immunity in the athletic population, Newsholm et al. (Newsholm. 2011) write in Part 18 of a 2010/11 series on purported ergogenic sport supplements in the British Journal of Sports Medicine:

Glutamine supplementation after exercise reduced the self-reported incidence of illness in endurance athletes. However, when glutamine was given to athletes to combat exercise-induced depletion of circulating glutamine, no effects were observed on the immune parameters studied, apart from reduced neutrocytosis and increased circulating IL-6.

But if the existing anecdotal evidence is not merely a result of placebo effects (If you spent 50 bucks on a big pot of l-glutamine you do want that stuff to work, don't you? And if each and every "pro" tells you it does, it should work, shouldn't it?) or an increased awareness of how healthy you have "become", now that you are taking supplemental glutamine (when you have in fact been healthy all along), dosing issues, the addition of other nutrients and most importantly, training type and intensity would have been taken into consideration to explain the inconsistency of respective trials.

Did you know that moderate training, in contrast to the bodybuilding "go heavy or go home" type of training, leads to "improved glutamine availability due to a positive balance between muscle synthesis and peripheral clearance", while physical inactivity can reduce glutamine synthesis and availability!

In this context, it is noteworthy that declining glutamine levels after / in the course of periods of increased training intensity have only lately been (re-)introduced as a potentially useful indicator of overtraining by Agostini & Biolo (Agostini. 2010). They point out that "[s]trenuous physical exercise as well as exhaustive training programs [which] lead to glutamine depletion due to lowered synthesis and enhanced uptake by liver and immune cells". Lower glutamine levels, on the other hand, have been "associated" (notice we do not have enough evidence for a causal relationship here) with compromised immunity. Immediate / continuous repletion of whole body glutamine stores (serum & tissue) via adequate dietary or supplemental intake could thus very well help to maintain immunity.

Image 3: BCAAs are not only way
more ergogenic, they may in fact
also be a more versatile source of
glutamine than l-glutamine, itself.

Personally, I find it telling that much of the positive data on glutamine supplementation for immune health comes from studies on endurance athletes from the early and late 1990s. If you consider the poor nutritional advice those athletes were given at that time, many of them were hardly getting enough protein along with the shitloads of carbohydrates they were told to eat. Now, someone who lacks essential amino acids, and more specificically BCAAs, for glutamine production, is of course at higher risk of 'running out of fuel for his immune system', especially if he exhausts his already compromised tissue stores by chronic endurance exercise.

Conversely, the group of athletes who consumes the largest amounts of supplemental glutamine, i.e. bodybuilders, is probably the one who will benefit least of all from additional l-glutamine in their diet. No wonder that Candow et al. who studied the effect of a standardized strength training protocol with or without a 0.9g/kg lean tissue mass glutamine supplement on strength, body composition and protein turnover in young athletes found "that glutamine supplementation during resistance training has no significant effect on muscle performance, body composition or muscle protein degradation in young healthy adults" (Candow. 2001). While this obviously does not say anything about immunity you may safely assume that the latter was not compromised in the first place and thus evidently would not have benefited from the roughly 50-60g of l-glutamine (certainly a "sufficient" dose ;-) the subjects in the Candow study consumed.

"Glutamine increases regeneration and improves muscle and strength gains"

My preceding remarks on the useful- respectively -lessness of glutamine supplementation in marathon runners and bodybuilders have already touched on one of the recurring themes of the Amino Acids for Super Humans series: What is essential and beneficial for athlete A in situation B may be ineffective for athlete B in situation B or even athlete A in situation A. The data (table 2) from studies, which evaluated the effects of oral glutamine supplementation on exercise-related parameters in humans ("+" indicates improvement; "#" indicates no effect; "-" indicates detrimental effect), substantiates this observation. 

Author(s)	Protocol	+/#/-	Main Result(s)
Castell. 1997	exhaustive exercise in middle-distance, marathon and ultra-marathon runners, and elite rowers, in training and competition 2x5g glutamine vs. maltodextrin 0, 2h post exercise	+ immunity	"[...] provision of oral glutamine after exercise appeared to have a beneficial effect on the level of subsequent infections [...] the ratio of T-helper/T-suppressor cells appeared to be increased in samples from those who received glutamine"
Bishop. 2000	review of intra-workout / -competition supplementation	#cortisol #immune	Consuming "carbohydrate [...] but not glutamine [...] during exercise attenuates rises in stress hormones, such as cortisol, and appears to limit the degree of exercise-induced immunosuppression"
Krzywkowski. 2001	bicycle exercise for 2 h at 75% of maximum O(2) 5x 3.5g glutamine vs. 3.5g maltodextrin at 0, 45, 90, 135, 170min post cycling	#immune	"no effect on lymphocyte trafficking, NK and lymphokine-activated killer cell activities, T cell proliferation, catecholamines, growth hormone, insulin, or glucose [...] Neutrocytosis was less pronounced in the glutamine-supplemented group, but it is unlikely that this finding is of any clinical significance"
Wilkinson. 2006	90 min cycling at 65% VO2max post-exercise oral CHO 1g/kg/h + 9.25g EAA + glutamine 0.3g/kg BW vs isoenergetic CHO-EAA w/out glutamine	#anabolism, +long-term recovery	Consuming "addition of glutamine to a CHO + EAA beverage had no effect on post-exercise muscle glycogen resynthesis or muscle protein synthesis, but may suppress a rise in whole-body proteolysis during the later stages of recovery"
Carvalho-Peixoto. 2007	15 athletes, 120 min (approximately 34 km) outdoor running 3 groups CHO g/kg/d + Gln 70 mg/kg/d; only CHO or only Gln in addition normal diet	+ammonia detox	"ammonia was not different for the first 60 min, but for the second hour [ammonia] was lower than in the control"
Wilkinson. 2006	90 min cycling at 65% VO2max post-exercise oral CHO 1g/kg/h + 9.25g EAA + glutamine 0.3g/kg BW vs isoenergetic CHO-EAA w/out glutamine	#anabolism, +long-term recovery	Consuming "addition of glutamine to a CHO + EAA beverage had no effect on post- exercise muscle glycogen resynthesis or muscle protein synthesis, but may suppress a rise in whole-body proteolysis during the later stages of recovery"
Favano. 2008	9 soccer players, cardiopulmonary exercise test + simulated soccer match, peptide glutamine (Gln) = 50 g of maltodextrin + 3.5 g of peptide glutamine or CHO alone 50 g of maltodextrin 30 min before test	+performance	"Total distance covered was 12750 [CHO] and 15571 [Gln]", i.e. +22% distance; "total duration of tolerance was 73 +/- 23 min when using CARBO and 88 +/- 24 min when using [Gln] (p<0.01)", i.e. +20% duration of tolerance"
Bassini-Cameron. 2008	prof. football players, Gln Alanine 100mg/kg, either short-term or long-term, immediately before exercise; intervals (n = 18) and continuous intensity (n = 12) exercise tests	#anabolism, +long-term recovery	"[...] results suggest that chronically supplemented Gln protects against exercise-induced hyperammonemia depending on exercise intensity and supplementation duration
Table 2: Some scientific data from human studies on oral glutamine supplementation from the last years ("+" indicates improvement; "#" indicates no effect; "-" indicates detrimental effect)

Despite the fact that the existing human data does not support the idea that athletes in general and weight trainers or fitness fanatics in particular would benefit from the tons of glutamine supplements that are sold year by year, some of the advertisment claims are in fact based on observations in petri dishes or animal models:

• In the petri dish, glutamine actually is the potent "cell volumizer" the advertisments would have it and its administration to isolated hepatocytes (liver cells) does in fact stimulates anabolic processes within the cells, which involve an increased synthesis of DNA, RNA, and proteins.
• It has also been found in cell studies that glutamine-induced cell swelling activates extracellular signal-regulated kinases and p38 (mitogen-activated protein kinase, MAPK), which are involved in stress response + adaptation and could thus facilitate muscle growth.
• Two grams of glutamine taken on an empty stomach have furthermore been shown to evoke an immediate growth hormone response, which - and this is the major caveat - is not only so minuscule that it is physiologically irrelevant; it also reduces the amount of growth hormone that is released after the sudden burst occurred, so that the overall AUC, the area under the 24h GH curve or, in other words, the overall 24h growth hormone production remains unaltered (similar effects have been observed for acetyl-l-carnitine (more on ALCAR in Part IV (2/3) of the AA for SH Series) and combinations of l-lysine and l-ornithine).
• And even the beneficial effects of parenterally administered alanyl-l-glutamine, an alanine + glutamine dipeptide, on (unfortunately) whole body insulin sensitivity are well established (Bakalar. 2006).

The reproduction or transfer of these effects from the respective model into real world results that would be relevant for the athletic practice have yet failed time and again and a mechanism which would explain the anecdotal evidence on the performance enhancing or muscle building effect of glutamine, which has repeatedly been confirmed by members of the bodybuilding and fitness world, could well be encapsulated within a fundamental physiological process that has acquired sort of a bad reputation lately: gluconeogenesis.

Did you know that in a 2010 study by van Hall et al. (Hall. 2010) a glutamine/carbohydrate mixture (0.8 g x kg(-1) body weight of glucose + 0.3 g x kg(-1) glutamine) failed to increase the rate of glycogen resynthesis in muscle over glucose alone. On the other hand, an isocaloric whey hydrosolate and even a wheat hydrosolate did (whey +20%; wheat +21%). What the study by Hall et al. confirms with respect to the regenerative effects of glutamine, is confirmed in terms of its effects on immune function, muscle protein breakdown and athletic performance by findings from Basset et al. (Basset. 2000), Hole (Hole. 2001) and Lehmkuhl et al. (Lehmkuhl. 2003), where the actual immuno-modulators, anti-catabolics and ergogenics were BCAAs and creatine, and the BCAA induced elevation of glutamine levels were corollary and not causative, and the addition of supplemental glutamine to creatine monohydrate without any effect on exercise performance.

In view of the current scare of everything carbohydrate-, god-forbid, insulin-related I hardly dare telling you that no other amino acid is so readily (ab-)used by your liver for glycogen production (=glyconeogenesis) as glutamine. This is especially true for doses that exceed the 2-5g range. They do not only provoke an accelerated glutamine clearance which is consistent with the activation of hepatic glutamine removal, but have also been shown to increase glucose formation in humans up to 7-fold (28g of glutamine infused in 4h time window; Perriello. 1997) at rest and to keep blood glucose levels up, glucose formation elevated (+24%) and glucose utilization increased (+16%) in a study, where dogs had received 12 micromol/kg/min glutamine intravenously during and after exercise (Iwashita. 2005).

Now, even if you are a carbophobic insulin-hater, this does not mean that you should flush your glutamine supply down the toilette. In view of the fact that even the marked increase in gluconeogenesis that was observed by Perriollo et al. was not accompanied by an increase in insulin or glucogon levels, glutamine may in fact turn out to be the ideal supplement for endurance athletes or dieting body builders or figure competitors who want to maintain healthy blood glucose levels on a low carb diet. For a sedentary person on a no-carb diet, or example, even 20–40g glutamine per day would probably be enough to fuel their glycogen demands.

Conclusion

Image 4: You do not always need supplements.
Oftentimes a nutritionally dense diet with a high
amount of protein will work at least just as well
as the latest and greatest amino acids supplement
you read about in your favorite fitness magazine.

The latter creative application of glutamine as a carbohydrate replacement aside, I am, based on the available data on the ergogenic effects of supplemental glutamine, inclined to subscribe to the conclusion of the authors of the BJSM Supplement Review (Newsholm. 2011) on glutamine who point out that

[...] there is no consensus or unifying concept to explain the efficacy of exogenous provision of glutamine alone on performance in athletes, although in combination with carbohydrate or other amino acids, significant improvements have been reported. 

Thus, notwithstanding its importance in many performance related physiological processes, an appropriately nourished human body is well able to synthesize more than enough glutamine from essential amino acids (and BCAAs in particular) to satisfy both everyday, as well as athletic demands. Consequently, athletes who wish to take advantage of the undeniably beneficial effects of adequately filled glutamine pools should give priority to the provision of adequate amounts of essential amino acids (EAAs), in general, and BCAAs, in particular. And despite the fact that the supplement industry would have you believe otherwise, most recreational athletes can easily satisfy their EAA demands by consuming a nutritionally dense high protein diet and an optional whey protein supplement.