MSM Cures Exercise Related Joint & Muscle Pain, But May Effect Immunity | Arginine Silicate Delivers, but Practically Relevant Data is Still Missing | ISSN Research Review '15 #5

Exercise induced joint and muscle pain - Can a few grams MSM help?

In this installment of the SuppVersity ISSN '15 Research Re- or rather Overview I couldn't really find a common theme. With two studies on MSM and one on arginine silicate you could probably best call it the "less researched supplement review".

Many people probably don't even know that MSM stands for "methylsulfonylmethane" and the notion that one could benefit from inositol-stabilized arginine silicate was - I openly admit that - complete news to me, too.

Read more about ISSN and other studies at the SuppVersity

Vitargo, Red Bull, Creatine & More | ISSN'15 #1

Pump Supps & Synephrine & X | ISSN'15 #2

High Protein, Body Comp & X | ISSN'15 #3

Keto Diet Re- search Update | ISSN'15 #4

The Misquantified Self & More | ISSN'15 #5

BCAA, Cholos-trum, Probiotics & Co | ISSN'15 #6

• The benefits of inositol-stabilized arginine silicate as a workout ingredient - Over the past years the way people thought and think about arginine has changed significantly. While it was originally considered a super-supplement that would increase pump, gains and vascularity, most recent studies on its effects on relevant markers of exercise performance and training adaptation yield similarly disappointing results as Gary Cooks honor thesis from 2015 in which he observed that neither arginine supplementation 20 minutes prior to exercise, nor arginine supplementation two hours post exercise had an effect on the increase in strength performance or hypertrophy following a 4-week resistance training regime (Cook. 2015).
  
  

  

  Only few studies show ergogenic effects of plain arginine. This one, however reports a sign. increase in to exhaustion in a group of elite wrestlers.

  With more and more consumers becoming aware of the lack of effect of regular arginine, supplement producers are forced to develop "alternatives" - alternatives that promise to finally do what regular l-arginine supplements promised to do: Boost your nitric oxide levels, exercise performance and overall gym experience. With inositol-stabilized arginine silicate (ASI; Nitrosigine®) there's a true newcomer that is set about revolutionizing the pre-workout supplement scene ... that's at least if we believe in what the patent holders tell us about the "new standard for pumped results" (manufacturer's homepage).
  
  In fact, ASI has been previously shown to enhance blood levels of arginine up to six hours post-dose and increase nitric oxide levels, acutely (Kahlman. 2014). In the long(er) term, Whether that would produce practically relevant increases in perceived intra-workout energy, muscle pump, and stamina, as well as post-workout muscle recovery was now the subject of a new study by Rood-Ojalvo et al. (2015).

Future (independent) research necessary: When it comes to supplement research it is absolutely normal that the effects of new products are initially tested by the ones who invent / produce it. In the long run, however, it would be nice to see the results of the study being reproduced by independent research... research that would also include actually meaningful (=performance or hypertrophy-related), objectively measurable study outcomes instead of subjective levels of perceived energy and (on their own) practically irrelevant increases in blood flow.

• The randomized double-blind placebo-controlled cross-over study study was conducted with 16 male subjects with limited exercise routines prior to participating in the study. The subjects took 1,5g/day of ASI or a placebo supplement daily for 4 days before they completed an intense leg extension exercise protocol to induce muscle soreness. Subjects then returned to the lab after 24, 48, and 72 hours for additional study measurements. After 72 hours, subjects repeated the leg extension exercise protocol to assess whether the provision of ASI (or placebo) had measurable effects on the recovery protocol.
  

  

  Figure 1: In spite of significant changes in blood flow velocity and leg circumference (which is interpreted as increased blood flow / hyperemia by the authors) the study at hand cannot prove practically relevant ergogenic effects of ASI simply because corresponding outcome variables were not assessed (Rood-Ojalvo. 2015).

  The scientists' analysis of the data they got produced two important results: Firstly, the 19-33 year-old subjects felt significantly more energetic and less fatigued (at least based on inertia sub-scores) on the 72 hour retest compared to placebo (p = 0.039). Secondly, the provision of the supplement lead to significant increases in leg circumference. Unfortunately, this increase in leg circumference is not a sudden muscle gain. Rather than that, the increased leg circumference appears to be a result of increased hyperemia (=increase of blood flow).
• In conjunction with the significant decrease in CK levels - a purported, albeit unspecific marker of muscle damage - in the ASI group at 24 (p = 0.040), 48 (p = 0.017) and 72 (p = 0.034) hours, the overall results of the study at hand do thus suggest that short-term supplementation with inositol-stabilized arginine silicate could have ergogenic effects. In the absence of meaningful outcome measures such as the number of reps (=volume) or the maximal weight lifted during the exercise tests, it would yet be premature to say that ASI is a proven ergogenic. 
• MSM for muscle and joint pain in marathoners and other athletes -- As Withee et al. point out in the introduction of the abstract to their poster presentation "[p]articipants in organized running commonly experience muscle and joint pain while training for and competing in distance events" for them a supplement that is able to reduce the pain associated with osteoarthritis could be a true game changer; and methylsulfonylmethane (MSM), a sulfur-based nutritional supplement, could be that supplement.
  
  Several previous studies have shown that MSM has anti-osteoarthritic and anti-inflammatory properties. Whether it would also help managing exercise-induced muscle and joint pain, effectively, was now the research question of a recent study from the National College of Natural Medicine in Portland (Withee. 2015). The design of the study is simple:

  "Twenty-two healthy females (n = 17) and males (n = 5) (33.7 ± 6.9 yrs.) were recruited from the 2014 Portland Half-Marathon registrant pool. Participants were randomized to take either MSM (OptiMSM®) (n = 11), or a placebo (n = 11) at 3g/day for 21 days prior to the race and two days after (23 total). Pain was recorded using a 100 mm Visual Analogue Scale (VAS) for both muscle pain (MP) and joint pain (JP) on a single questionnaire. Participants completed the questionnaire at five time points. Baseline levels (T0) were recorded approximately one month prior to the race. Post-race pain levels were recorded at 15 minutes (T1), 90 minutes (T2), 1 Day (T3), and 2 days (T4) after race finish. Data were analyzed using linear mixed models controlled for baseline, with time point as a repeated factor. Simple contrasts compared post-race time points to baseline, and Student's t-tests assessed between-group time point comparisons" (Withee. 2015)

  Unfortunately, this cannot be said for the study results, which showed nothing but a trend of lower pain levels in the MSM group - with non-significant time-by-treatment effects in either of the groups.
  

  

  Figure 2: Muscle and joint pain  15 minutes (T1), 90 minutes (T2), 1 Day (T3) after half-marathon race with methylsulfonylmethane (MSM | 3g/day) or placebo supplementation (Withee. 2015)

  In view of the fact that the provision of the 3g of MSM did result "in nearly significantly lower MP at T1 (MSM = 27.3mm vs. placebo = 49.8mm, p = 0.063), and lower MP at T2 (27.1mm vs. 40.0mm; p = 0.300), and T3 (30.0mm vs. 41.9mm; p = 0.306)" (my emphasis in Withee. 2015), as well as similar changes in joint pain (see Figure 2), it does still appear warranted to conclude that MSM supplements (3g/day) may be worth trying for anyone suffering from persistent joint and/or muscle pain after workouts.
• MSM as an inflammatory cytokine modulator -- While the previously discussed study by Withee et al. (2015) clearly indicates that MSM supplementation helps managing the level of exercise-induced inflammation, Withee et al. did not investigate the mechanism that was responsible for their observations. A recent study from the University of Memphis, however, did just that: In said study, Godwin et al. determined the effect of MSM on lipopolysaccharide (LPS) - induced inflammatory mediators after a single bout of acute eccentric exercise.
  
  To do so, they had five recreationally active, healthy men consume either 3g/day of MSM or a placebo supplement for 28 days. At the end of the supplementation program, a single bout of acute exercise (10 sets of 10 repetitions of eccentric knee extensions) was performed and blood samples were collected (immediately = 0 h, as well as 24 h, 48 h and 72 h post exercise) and analyzed.
  
  

  

  Do you remember that MSM can also act as a GH booster & bone builder | more

  The most significant results of the analysis are hardly surprising: The supplementation of MSM blunted the increase in the systemic levels of inflammatory cytokines (IL-6 and IL-1β) immediately after exercise.
  
  What is surprising, though, is the fact that the inflammatory response to LPS exposure in an ex-vivo study with blood that had been drawn at various time-points during the study shows a "dramatic increase in inflammatory cytokine secretion (IL-6, IL-1β and TNF-α) only after exercise for samples that was exposed to MSM" (Godwin. 2015).
  
  So what does that mean - practically speaking? Well, the authors are certainly right, when they point out that ...

  "[t]his response is specific to the stimulation with LPS as secretion of LPS-non responsive proteins is not increased, as evident by the stable levels of IL-17a [... and thus suggestive of the fact that] MSM is able to reduce the initial cytokine surge that is induced by acute exercise, while allowing for an efficient response to infectious stimuli after a single bout of acute exercise" (Godwin. 2015).

  On the other hand, this assumption stands in contrast to the 2-3 fold increase in IL-10 production after LPS stimulation for the subjects in the MSM group whose pre-exercise levels of the IL-10 levels before exercise. Previous research did after all suggest that greater IL-10 production my be the motor of the exercise induced "depression of immunity commonly reported in athletes engaged in high training loads" (Handzlik. 2013). Whether the chronic use of MSM supplements entails an increased risk of infection may thus warrant further investigations.

3x 1.3g/day cordiceps synensis can significantly increase time to exhaustion and have (individually different) beneficial effects on the ventilatory threshold (Hirsch. 2015).

Two more to go... two more studies that is: While the total number of ISSN '15 studies I haven't discussed or at least mentioned in this series yet is larger than two, there are only two studies I'd like to single out before the end of this installment of this Suppversity series. The Cordyceps synensis study by Hirsh et al. who were able to show that 4g of the mushroom can improve oxygen kinetics, and peak power non-significantly, as well as time to exhaustion significantly in recreationally active subjects who completed  a maximal graded exercise test, 6 min sub-maximal cycle test, and 3 min all-out cycle test, each separated by at least 24 hrs when the supplement is consumed chronically, i.e. in thee servings of 1.3 g equally spread across the day for three weeks (Hirsch. 2015).

Also worth mentioning, but in the absence of hard evidence of causality hardly worth discussing in much detail is Marc Bubbs' observation that basketball players who are training at high-intensity "seem more likely to have insufficient levels of vitamin 25(OH)D" (Bubbs. 2015) - if a follow up shows that normalizing these levels with supplementation will have performance enhancing effects, though, this would be really news-worthy | Comment on Facebook!

References:

• Bubbs, Marc. "Observational case study-Vitamin 25 (OH) D status of professional basketball players and its impact on athletic performance and recovery." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P55.
• Cook, Gary. The Effects of Chronic Arginine Supplementation on Muscle Strength and Hypertrophy Following Resistance Training. Diss. Ohio Dominican University, 2015.
• Godwin, Simone, et al. "MSM enhances LPS-induced inflammatory response after exercise." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P48.
• Handzlik, Michal K., et al. "The influence of exercise training status on antigen-stimulated IL-10 production in whole blood culture and numbers of circulating regulatory T cells." European journal of applied physiology 113.7 (2013): 1839-1848.
• Hirsch, Katie R., et al. "Chronic supplementation of a mushroom blend on oxygen kinetics, peak power, and time to exhaustion." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P45.
• Kalman, Douglas, et al. "A clinical evaluation to determine the safety, pharmacokinetics and pharmacodynamics of an inositol-stabilized arginine silicate dietary supplement in healthy adult males.(LB418)." The FASEB Journal 28.1 Supplement (2014): LB418.
• Rood-Ojalvo, S., et al. "The benefits of inositol-stabilized arginine silicate as a workout ingredient." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P14.

Synephrine More Ergogenic, Than Thermogenic? Pump Supps Revisited - L-Arginine, L-Citrulline and Respective Whey-Peptides & -Nitrates | ISSN Research Review '15 #2

Synephrine, arginine, citrulline - Which pre-workout ensures that you're "on fire"?

As I pointed out previously, my initial idea to cherry pick only the most interesting study results that were presented in form of of poster presentations at the Twelfth International Society of Sports Nutrition (ISSN) Conference and Expo in 2015 didn't work out. The number of interesting studies is is simply too much for a single SuppVersity article to discuss them all.

Accordingly, I am now posting the 2nd serving of what is going to be a multi-part series of articles with brief discussions of the most significant results of the >20 studies and short references to those that didn't make the SuppVersity cut in this, previous and future installments of this series for one reason or another.

Read more about ISSN and other studies at the SuppVersity

Vitargo, Red Bull, Creatine & More | ISSN'15 #1

Pump Supps & Synephrine & X | ISSN'15 #2

High Protein, Body Comp & X | ISSN'15 #3

Keto Diet Re- search Update | ISSN'15 #4

The Misquantified Self & More | ISSN'15 #5

BCAA, Cholos-trum, Probiotics & Co | ISSN'15 #6

• Synephrine More Ergogenic Than Thermogenic? There was not just one, but two poster presentations and a full paper that has been published only days ago on synephrine containing supplements at the ISSN meeting and on the ISSN website, respectively. Synephrine? Yes, that's the supplemental non-starter, ah... I mean allegedly powerful fat burner from orange peels. The one with promising fat loss results in rodents, but discouraging results in practice.
  
  Luckily, the studies that were presented in form of posters by scientists from the Texas A&M University (Jung. 2015 & Dalton. 2015) at the ISSN meeting did not deal with synephrine as fat burner. Rather than that, Jung et al. and Dalton et al. took a look at the short- and long-term safety of synephrine as a pre-workout. A pre-workout that contained either 3g beta alanine, 2g creatine nitrate, 2g arginine AKG, 300mg N-acetyl tyrosine, 270mg caffeine, and 15mg Mucuna pruriens, alone (PLA) or the same baseline ingredients and synephrine.
  

  

  Figure 1: Number of reps on sets 1-3 & 4-6 in the control and treatment conditions (Ratamess. 2015)

  Now, the fact that some synephrine in your preworkout won't kill you is not really exciting. I have to admit that. What is exciting... at least sort of, though is the fact that the questionable thermogenic turned out to be an effective ergogenic in the already published and thematically related study by Ratamess and colleagues (Ratamess. 2015). A study that shows that p-synephrine of which previous studies indicate that it is a potent, but highly selective β-3 adrenoreceptor may nor be the best fat burner (the good old ephedrine was a pan-receptor activator and clenbuterol & co target the β-3 receptor, maybe that's also why the fat loss results are rather disappointing) , but at least an underestimated ergogenic.

Is p-synephrine different from synephrine? That's a good question without a clear question. Most supplements that list synephrine on the label actually contain P-hydroxy-α-{methylaminomethyl}-benzylalcohol aka p-synephrine, a protoalkaloid compound that differs from m-synephrine and o-synephrine structurally and comes in form of to stereoisomers in most supplements - the l-enantiomer and the d-enantiomer as the racemate d,l-synephrine. While the latter have been shown to be present in bitter orange, other forms, like the m,s-isomer may are suspected to be adulterations from synthetic phenylephrine supplement producers use to "spike" (Allison. 2005) their products (I assume this was not the case with the samples the researchers in the study at hand used, but the chaos wrt to the types of synephrine puts a huge "?" behind the assumption that you'll see the same effects from any given synephrine or synephrine + caffeine supplement. 

• As the data in Figure 1 goes to show you, the p-synephrine supplement, which was administered to twelve healthy, college-aged men at a dosage of 100mg either alone (S) or in conjunction with 100 mg caffeine (SCF) for three days. On the day on which the subjects participated in a standardized resistance exercise protocol consisting of 6 sets of squats for up to 10 repetitions per set using 80 % of their one repetition-maximum (1RM) with 2 min of rest in between sets, the supplement was ingested 45 minutes before the workout. In comparison to the placebo treatment synephrine alone triggered a significant increase in total repetitions and volume load. When synephrine was combined with 200 mg of caffeine, it also increased the mean power and velocity of squat performance. What did not change in response to either synephrine alone or caffeine and synephrine, though, were the blood lactate levels or the rate of perceived (RPE) exertion the subjects reported on the usual visual analogue scales.
  
  For me personally, that's a surprising result. For the scientists it "indicate[s that] supplementation with S and SCF can enhance local muscle endurance during resistance exercise" (Ratamess. 2015); and I have to admit: They are right. One thing you should keep in mind, though, is that unlike caffeine, where you often see reductions in RPE and thus an effect you will feel, synephrine will - even if it works - do its purported "magic" more subtly.
• The Latest on "Pump Supplements" - Creatine, Arginine, Citrulline, Nitrates -- To make sure that this series is not turning into a 12-part article, I will address the results of Moon's, Suzuki's and Vogel's results in one item (since Moon's paper basically summarizes the results of studies by Falcone and Joy, I won't discuss those separately) .
  
  

  

  Figure 2: Increases in blood flow volume (BFV) 33 minutes after the ingestion of 1.87g of RC, 3.67g of CP (citrulline content 1.87g), 1.87g of RA, or 3.07g of AP (arginine content 1.87g) before 3 sets of 15 arm curls (Moon. 2015).

  Moon et al.'s comparison of citrulline's and arginine's ability to increase the exercise-induced vasodilation and blood flow yielded unsurprising results that confirm that citrulline-based ingredients are more effective than arginine-based ingredients for modulating vasodilation and blood flow. Now that alone wouldn't be news-worthy if the scientists had not tested the effects of both, rawe L-citrulline (RC) and raw L-arginine (RA) and, citrulline and arginine bound to a whey peptide (CP and AP, respectively).
  
  I guess I am not going to surprise you, when I tell you that regular arginine was the worst vasodilator in this quartet. What is more surprising, though, is the extent to which the peptide bonding increased the vasodilating effects of regular citrulline and even arginine. With the the former producing 2x higher increases in vessel diameter and 9% higher increases in blood glow volume than regular citrulline (let's not even mention regular arginine | see Figure 2) the effects are pronounced enough to be potentially "feelable" and "visible" during a workout.
  
  

  

  Citrulline & Glutathione - GSH Amplifies & Prolongs CIT's NO Boosting Effects During + After Biceps Workout | learn more.

  Against that background I would be curious to see, whether the likewise recently reported performance enhancing effects of citrulline Suzuki et al.'s observed in twenty two well-trained young men who consumed 2.4 g / day of L-citrulline or placebo for 7 days and they took 2.4 g of L-citrulline or placebo 1 hour before 4 km cycling time trial on day 8 would be enhanced by bonding citrulline to whey peptides.
  
  I mean, if citrulline-whey-peptides appear to offer the same effects citrulline does, but at a higher efficacy, their beneficial effect on cycling time trial performance of which the Suzuki et al. argue that it was mediated by an up-regulation of plasma NO availability should be superior to that of raw citrulline, as well, right?
  
  And now that we are already talking about what really matters, i.e. performance enhancements, not increases in blood flow, it would also be interesting to see a follow up on the last "pump supplement" study to be mentioned in this installment of the ISSN Research Review: A study by Vogel et al.'s on the vasolidating effects of an arginine-nitrate based pre-workout supplements that shows significant increases in brachial artery diameter. Increases that are quantitatively similar to those Moon et al. observed for citrulline-whey-peptides in the previously discussed study. That does not mean, though that they are equally effective, though. To be able to say that we would need a study in which both agents are compared head-to-head. Unless this study is done and a follow up on Vogel's study proves that the increases in blood flow will actually produce significant performance gains, the only thing I can say about arginine nitrate is: It's interesting, but with respect to its ergogenic effects more studies have to be done.

You don't believe citrulline can do anything for you? Check this out: 8g/day Citrulline Increase Leg Workout Performance - More Reps on Leg Press, Hack Squat & Leg Ext. in Exp. Gymrats (more)! It is thus by no means useful for "cosmetic pumps", only 

Studies that didn't make the cut in this issue are Brooke Bouza et al.'s study on the exercise and calorie information on menus (Bouza. 2015) as well as O'Conner et al.'s tart-cherry study (O'Connor. 2015). That's not because there were methodological issues or something. It's much simpler: The notion that "exercise and calorie information on menus is not enough to improve food choices in Hispanic adults" (Bouza. 2015) is about as unsurprising as the word "potentially" (O'Connor. 2015) in the conclusion of O'Connor's study is daunting. And by the way, now that you know that tart cherry "potentially increases running performance and attenuates post-race markers of inflammation" you actually know the most relevant finding of O'Connor's study, right? | Comment on Facebook!

References:

• Allison, D. B., et al. "Exactly which synephrine alkaloids does Citrus aurantium (bitter orange) contain?." International journal of obesity 29.4 (2005): 443-446.
• Bouza, Brooke, et al. "Exercise and calorie information on menus is not enough to improve food choices in Hispanic adults." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P3.
• Dalton, R., et al. "Safety and efficacy of a pre-wrkout dietary supplement with and without synephrine." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P5.
• Falcone, Paul H., et al. "Acute hemodynamic effects of L-arginine, arginine nitrate, and arginine peptide on exercise-induced vasodilation and blood flow in healthy men." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P10.
• Joy, Jordan M., et al. "A comparison of raw citrulline and citrulline peptide for increasing exercise-induced vasodilation and blood flow." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P18.
• Jung, Y. P., et al. "Effects of 8 weeks pre-workout dietary supplement ingestion with and without synephrine on blood chemistry panel." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P4.
• Moon, Jordan R., et al. "A comparison of citrulline and arginine for increasing exercise-induced vasolidation and blood flow." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P6.
• O'Connor, A., et al. "Short-term powdered tart cherry supplementation encircling an acute endurance challenge potentially increases running performance and attenuates post-race markers of inflammation." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P7.
• Suzuki, Takashi, et al. "Oral L-citrulline supplementation enhances cycling time trial performance in healthy well-trained males." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P52.
• Vogel, Roxanne M., et al. "Acute hemodynamic effects of a multi-ingredient performance supplement on brachial artery vasodilation and blood flow volume following elbow flexion exercise in healthy young men." Journal of the International Society of Sports Nutrition 12.Suppl 1 (2015): P28.

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 ;-)

Want to get stronger, bigger, faster and leaner, but not sick? Periodize appropriately!

30% More on the Big Three: Squat, DL, BP!

Block Periodization Done Right

Linear vs. Undulating Periodizationt

12% Body Fat in 12 Weeks W/ Periodizatoin

Detraining + Periodization - How to?

Tapering 101 - Learn How It's Done!

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 reduction of 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.

Unexpected Performance Increments in Elite Wrestlers in Response to Well-Timed Arginine Supplementation: 5.8% Increased Time to Exhaustion, No Recution in O2 Cost!

Science is still wrestling with evidence in favor vs. against l-arginine

Actually the study at hand is not really exciting, the researchers from the Near East University Medical School in Cyprus recruited nine male national and international level wrestlers put them on more or less standardized diets, forbid them to work out and or use caffeine, stimulants or other ergogenic supplements and fed them 1.5g arginine per 10kg body weight (that's 12grams for someone with a body weight of 80kg).

Aside from the dosage, which would be on the higher side compared to the average arginine trial, there were no significant differences to study protocols you know.

Lear more about L-arginine at the SuppVersity!

No N.O. W/ Arginine

Arginine vs. High Lipids

Arginine Blunts GH?!

Arginine for Satiety?

Arginine vs. T2DM

Arginine for Fat Loss?

The subjects reported to the laboratory fasted in the AM, they have followed identical diets before both the active and the placebo trial and they had to perform one of those arduous pedal until you drop exercise tests on a cycle ergometer...

There was one difference, however. The subjects were not allowed to start working out immediately after they'd washed down the arginine / placebo supplement. Instead, they had to wait for sixty minutes for the arginine peak in plasma (Gannon. 2002).

Figure 1: Time to exhaustion and lactate levels increased, the VO2 costs of which you could expect that they decreased and would thus allow for the increased time to exhaustion, on the other hand, didn't change (Yavuz. 2014)

And voila! As you can see in Figure 1, Yavuz, Turnagol and Demirel observed a significant performance increase in the arginine trial.

In that, it is quite astonishing that these improvements occurred in the absence of changes in VO2 consumption. A reduction in O2 cost, as it was reported by Bailey et al. (2009) would after all be the most obvious explanation of the ergogenic effects of arginine.

Suggested Read: Arginine a BAT Building WAT Killer & Repartitioning Agent? Plus: The Arginine Enriched Biscuits Diet ;-) | read more

Bottom line: Previous results of studies with arginine supplementation on performance are rather inconsistent and it is difficult to say whether these differences can be explained by the length of the supplementation period, the combination of arginine with different components, different doses of arginine, different exercise protocols, different fitness levels of subjects (endurance trained athletes, physically active healthy men, or combat sports athletes as in the study at hand). Even the hitherto overlooked exact timing of supplementation and workout could make all the difference - so in case you still have a truckload of arginine lying around at home, remember to take it on an empty stomach and 60 minutes before your workouts.

Reference:

• Bailey, Stephen J., et al. "Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans." Journal of Applied Physiology 107.4 (2009): 1144-1155.
• Gannon, Mary C., Jennifer A. Nuttall, and Frank Q. Nuttall. "Oral arginine does not stimulate an increase in insulin concentration but delays glucose disposal." The American journal of clinical nutrition 76.5 (2002): 1016-1022.
• Yavuz, H. U., H. Turnagol, and A. H. Demirel. "PRE-EXERCISE ARGININE SUPPLEMENTATION INCREASES TIME TO EXHAUSTION IN ELITE MALE WRESTLERS." Biol. Sport 31 (2014): 187-191.

L-Arginine - 6g/Day Boost Cholesterol- & Non-Esterified Fatty Acid Lowering Effects of Resistance Training. Are Classic Pre-Workouts Actually "Health Supplements"?

Lifting will improve your blood lipids, l-arginine will boost the effect.

In the spirit of Tuesday's post on the potential negative effects of nitrate supplements on weight loss (learn more + see box below for some important clarifications), I would like to invite you to take a look at the effects of "short-term  L-arginine  supplementation  on  lipid  profile  and  inflammatory proteins after acute resistance exercise in overweight men" as they are about to be reported in one of the future issues of e-SPEN, the European e-Journal of Clinical Nutrition and Metabolism by Nascimento et al. (Nascimento. 2014) - it's not essentially new, but actually quite a nice reminder of the fat that what I said about l-arginine in the nitrate article was not all made up.

An addendum to the nitrate study: Even a persistent 5% reduction in RMR would not necessarily inhibit weight loss + you can argue that your body needs less energy / oxygen, because it works more effectively and contrary to common believe that's what a true ergogenic should do!

In the introduction to the said article, I already hinted at and linked to the potential weight loss benefits of l-arginine. In spite of the fact that it is literally useless as an NO-booster (remember without increase in NOS, the enzyme that produces NO from arginine, simply piling up more arginine in your blood will only lead to increases in uric acid), previous studies have already shown that L-arg improves the metabolic profile of people with suboptimal health status.

• Schulze et al.. for example, observed that l-arginine speed up the triglyceride-lowering effect of simvastatin in patients with elevated plasma triglycerides (Schulze. 2009)

• El-Kirsh et al. found that both, L‐arginine and L‐citrulline supplementation ameliorated the biochemical parameters and blunted arthesclerotic lesions in high‐fat and high‐cholesterol‐fed rats (El-Kirsh. 2011)

Other studies report beneficial effects on blood pressure and - as discussed in the anti-diabetes series - an ameliorating effect on the blood glucose levels of diabetic and/or insulin resistant individuals (McKnight. 2010; Dong. 2011).

So, the results of this most recent study don't really come as a surprise

In view of what we already knew about l-arginine, the results of the Nascimento study, i.e. reductions in  LDL cholesterol and NEFA levels, in response to the ingestion of 3x2g of pure l-arginine per day in this double blind, randomized crossover study don't come as a surprise.

Figure 1: Changes in triglycerides, total & LDL cholesterol and NEFA levels in response to exercise, only (control) and exercise + arginine (arginine) supplementation; figures in boxes ind. inter-group diff. (Nascrimento. 2014)

What's "news", though, is the interaction with exercise that sheds a whole new light the good old NO-Xplode (learn more, but keep in mind that one characteristic feature of this products is and was being totally underdosed) and its identical clones! I mean, who would have expected that he was buying a health supplement that potentiates the beneficial effects of exercise, in this case...

• 

  The official SuppVersity Supplement Shoot-Out!
  The longstanding veteran, NOXplode AVPT,
  is challenged by a clone of its own, 
  NOXplode 2.0 Advanced Strength -
  which will be the last pre-workout standing?

  four acute, machine-based resistance training sessions
• stretching + general warm-up and cool down before / after sessions
• three sets of 12 repetitions; 60% of the 1RM; 60s rest between sets
• starting with large, ending with small muscle groups
• large muscle groups: Chest press, leg press, pull down, leg extensions
• small muscle groups: Deltoid machine, leg curl, biceps curl, triceps pulley

...on the potentially artherogenic low-density lipoprotein (LPL) and the amount of pro-diabetic non-esterified fatty acids in his bloodstream? You did? Well... I should have anticipated that, Mr & Mr Smar Alec ;-)

There is one question left to answer: What exactly is the mechanism here? I know that some of you won't care - as long as it works - but let's be honest, wouldn't it be nice to know? Well, acute and chronic exercise increase have already been shown to increase the activity of lecithin-cholesterol aciltransferase (L- CAT), the enzyme responsible for the cholesterol ester transfer to HDL, which will then evacuate the cholestrol from the circulation. If this effect is either increased or the transport facilitated by l-arginine, this would explain the reduction in LDL the researchers observed in the study at hand.

Figure 2: The short-term improvements in adiponectin Nascrimento et al. observed stand in line with the well-known long-term improvements in blood glucose management.

Moreover, studies by Tan et al. (2011) suggest that L-arginine will have direct effects on the expression of fat-metabolic genes in skeletal muscle and white adipose tissue, which favor lipogenesis in the muscle (not a problem if those lipids are subsequently burned as fuel during workouts) and a reduced storage of fat in the adipose organ. In conjunction with its proven ability to stimulate mitochondrial biogenesis and brown adipose tissue development (McKnight. 2010) and the previously discussed effects on WAT,  hyperphagia,  improved insulin sensitivity and - much contrary to nitrate (learn more) - increased energy expenditure (albeit only on low protein diets; Clemmensen. 2012). In sum these effects would appear to be profound enough to explain the observations in the study at hand, and those I reported in previous SuppVersity articles on l-arginine - specifically those discussing the potential fat burning (more) and anti-diabetic / glucose lowering effects (more).

Whether that's reason enough for you to begin supplementing again, is yet probably a question of your current metabolic state... if you are by no means like the seven overweight, hypertensive men, non-smoking and sedentary with a mean age of 46±5 yrs and a body weight of 93.1±12.0 kg, ain't insulin resistance, or have high cholesterol levels, it's pretty unlikely that you will see huge benefits.

References:

• Clemmensen, Christoffer, et al. "L-Arginine improves multiple physiological parameters in mice exposed to diet-induced metabolic disturbances." Amino acids 43.3 (2012): 1265-1275.
• Dong, Jia-Yi, et al. "Effect of oral L-arginine supplementation on blood pressure: a meta-analysis of randomized, double-blind, placebo-controlled trials." American heart journal 162.6 (2011): 959-965.
• El‐Kirsh, Amal Ashmawy Ahmed, et al. "The effect of L‐arginine or L‐citrulline supplementation on biochemical parameters and the vascular aortic wall in high‐fat and high‐cholesterol‐fed rats." Cell biochemistry and function 29.5 (2011): 414-428.
• McKnight, Jason R., et al. "Beneficial effects of L-arginine on reducing obesity: potential mechanisms and important implications for human health." Amino acids 39.2 (2010): 349-357.
• Schulze, Friedrich, et al. "L-Arginine enhances the triglyceride-lowering effect of simvastatin in patients with elevated plasma triglycerides." Nutrition research 29.5 (2009): 291-297.
• Tan, Bie, et al. "Dietary L-arginine supplementation differentially regulates expression of lipid-metabolic genes in porcine adipose tissue and skeletal muscle." The Journal of nutritional biochemistry 22.5 (2011): 441-445.