NAC Lowers DOMS, Initially, but on Day 5-6 it Makes Things Worse | Plus: Putative Performance Benefit is Negligible

In the long run, choking the exercise-induced fire too much is going to negate all the cherishable benefits of working out.

As a SuppVersity reader, you know what hormesis is and are aware that the proinflammatory assault of exercise, is an essential stimulant to musculoskeletal adaptation - a number of human and dozens of animal experiments show: if you quell the production of pro-inflammatory reactive oxygen species with high doses of vitamin C and E the growth and health response to exercise will be impaired. And vitamin C + E are not the only radical scavengers with this side effect.

In 2013, I wrote about a study that clearly demonstrated how N-acetyl-l-cysteine aka NAC "Reduces Inflammation, Muscle Injury & Cytokine Expression, but Impairs Anabolic Signaling, Satellite Cell Activity and Recovery" (re-read it) - keep that in mind before getting overly excited.

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Hence, NAC supplements shouldn't be used chronically. To control the inflammatory response to a workout and be able to return to the grind earlier, however, many people still rely on its noticeable ability to reduce early onset of DOMS (deep onset muscle soreness - learn more).

Is taking NAC ever a good idea for athletes?

Well, the good news for NAC lovers is: When used during a short competition, sportsmen and -women can actually benefit from the anti-DOMS effects, a recent study from the University of Auckland (Rhodes 2018) confirmed when it investigated...

"whether NAC supplementation decreases muscle soreness and enhances performance in a semi-elite sport setting [as well as] adverse effects and the tolerability of oral NAC supplementation" (Rhodes 2018).

The bad news is that using NAC for that very purpose won't just impair long-term gains, it would also backfire in terms of the what one could call a delayed DOMS response (if DOMS wasn't already delayed onset muscle soreness, obviously) on day 5-6 of the recovery period.

Figure 1: Schematic overview of the experimental design. Preliminary YYIRT-L1 performance measures were taken during preseason training, and post-supplementation performance measures were performed on days 5 and 6 of supplementation (NAC or placebo). Side effects and subjective muscle soreness were monitored through a daily TXT message during the supplementation period. NAC = N-acetylcysteine (Rhodes 2018).

That's at least what Rhodes' et al's observation that the initial "likely protective effect" (−19% ± 27%) on subjective muscle soreness of the 28 semi-professional, semi-elite male rugby players (age = 20.4 ± 0.9 yrs, height = 182.3 ± 7.4 cm, weight = 103 ± 12 kg, Yo-Yo Intermittent Recovery Test Level 1 [YIRT-L1] = 17.14 ± 1.73 level) who participated in the study, turned out to be reversed after 5-6 days of supplementation with 1g of NAC to when the authors observed a "very likely harmful effect" (71% ± 59%).

Figure 2: Running times (lower = better) and subjectively measured muscle soreness before during and at the end of the 6-day intervention with 1g of NAC in 28 semi-professional, semi-elite male rugby players (Rhodes 2018).

The effects on the actual exercise performance during the shuttle-run, on the other hand, were negligible - yes, this means you can safely ignore them. Everbody can tell that by looking at the running times in Figure 2, ... and yes, I don't care that the results of the “sportsci” parallel group trial spreadsheet (Hopkins 2015) suggest a "likely beneficial performance effect on maximum shuttle sprint time (2.4%; 90% confidence limit ± 4.8%)".

Whether more helps more is not clear! What is clear, though, is that 2 and more grams of NAC are more prone produce side effects in form of diarrhea, nausea, vomiting, and headache. You should furthermore remember that hormesis is all about managing the exercise stress - not annihilating. If you're using NAC, using the lowest effective dose should thus always be your goal.

To be fair, I should point out that the authors refrain from claiming to have a found a practically relevant performance benefit, when they write that..."this study was unable to demonstrate a clear effect of 1 g NAC on total time to complete a broken bronco exercise protocol" - that this was due to the low dosage of NAC, which is what they claim right after the cited passage, though, sounds a bit biased; and that despite the quoted results from a 2011 study by Cobley et al. (Cobley 2011), who gave their participants a higher dose of 50 mg/kg/day and observed an increase in YYIRT-L1 performance over time, with the greatest performance enhancement seen on the last testing session (three sessions in total).

When it comes to choosing whether and at which dose to use NAC (or vitamin C and vitamin E) you must consider hormetic dose-response relationship between stress exposure (X-axis) and adaptational response (Y-axis). Stimulatory effects occur in the low-dose region at the left of the no-observed-effects-level (NOAEL), whereas adverse effects occur in the high-dose region at the right of the NOAEL - The higher your baseline stress the more likely you'll benefit from antioxidants by reducing the background noise and enhancing the signal:noise ratio (Agathokleous 2018)

Overall, we need more research before we can - with some confidence - advice athletes to consume (high dose) NAC supplements during phases of intense competition; and that is particularly true for the purported recovery- and performance-enhancing effects semi-elite athletes are supposed to experience during exercise sessions with a high turnaround rate.

Learn more about hormesis

Taking NAC right before or during a meet or competition may still make sense -- I wouldn't totally exclude that there is a dosage effect, though, accordingly higher dosages (5g vs. 1g) should be recommended to those who want to (ab-)use NAC strategically during what Rhodes et al. aptly describe as "periods of anticipated high energy turnover with limited recovery time, such as during tournaments, competitions, or back-to-back hard training sessions" (Rhodes 2018).

During the training/off-season, however, it would be madness to interfere with ROS formation and IL-6 release as they have been found to be the real drivers of the adaptive response you're training for... ah, and by the way: To write "I take my NAC away from my workout" in the comments, will only expose your lack of knowledge about the way(s) your body functions. It's not going to help you soothe your conscience and make you feel good about a habit (=taking your high-dose NAC supplements religiously) that's almost certainly going to impair your gains - if you actually know what you're doing, however, and want to use NAC strategically before/during a meet or a short tournament, go for it but mind the side effects (test your individual tolerance before ending up in bed with a headache or on the toilette with diarrhea during the competition) | Comment!

References:

• Agathokleous, Evgenios, Mitsutoshi Kitao, and Edward J. Calabrese. "Environmental hormesis and its fundamental biological basis: Rewriting the history of toxicology." Environmental research 165 (2018): 274-278.
• Cobley, James N., et al. "N-Acetylcysteine’s attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations." International journal of sport nutrition and exercise metabolism 21.6 (2011): 451-461.
• Rhodes, etal. "Acute Effect of Oral N-Acetylcysteine on Muscle Soreness and Exercise Performance in Semi-Elite Rugby Players". Journal of Dietary Supplements (2018).

Taurine Pumps Up Strength & Recovery in Response to Eccentric Curls. NAC Decreases Peformance & Boosts Fat Oxidation!? Exercise Reduces, Caloric Restriction Increases Inflammation. Carnitine Rescues Fast Twitch Muscle

Blood glucose alone would not last for 90s of running up the stairs.

80 minutes! That's the SuppVersity Figure of the Week and the impressive timespan you could (theoretically) fuel your energy demands during exercise at 70% of your VO2max from your muscle glycogen stores.

The latter hold the energetic equivalent of ~1,500kcal and are thus an almost 40x larger reservoir of energy than the tiny amounts of glucose that's floating around in your bloodstream (data based on Gleeson. 2008).

If you had to rely on that alone, you would pass out after 2 mins of the previously mentioned exercise at 70% VO2max.

Obviously no workout is going to be fueled 100% exclusively by glucose/glycogen, so that you can still use the amount of energy your body stores in the fat cells (~93,000kcal) and in form of tissue proteins (~49,000kcal) and keep running for another 7,400 minutes or 5.13 days... theoretically

Enough of the figures let's get to some recent research results

• 

  You want the boost without the buzz? Hit the right taurine / caffeine ratio to avoid the stim crash & sleeplessness (learn how)

  Taurine for increased strength and recovery during and after eccentric biceps curls (Acordi da Silva. 2013) In a recent study researchers were able to show that the provision of taurine for 14 days before a standardized eccentric exercise regimen comprising 3 sets of eccentric biceps curls on the Scott bench that were performed at  80% of the 1-RM to total failure resulted in significant increases in strength levels and thiol total content of the muscle, as well as a decrease in muscle soreness, lactate dehydrogenase level, creatine kinase activity and oxidative damage (xylenol and protein carbonyl) after the workouts.
  
  Since the activity of the antioxidant enzymes (superoxide dismutase, catalase, and gluthatione peroxidase) and inflammatory markers (tumor necrosis factor, interleukin (IL) -1 beta, and IL10) in the blood of the twenty-one participants (mean age of 21 ± 6 years, weight of 78.2 ± 5 kg) were not altered, decreases in muscle growth as they have been reported for NAC, only recently are not likely to occur. 

• 

  CLA in pomegranate? Not really, but the CLnA in the seeds of the fruit may be even more potent (learn more)

  NAC increases fat oxidation, but compromises performance during HIIT cycling (Trewin. 2013) Talking about NAC another recent study conducted by Adam J. Trewin, Aaron C. Petersen, Francois Billaut, Leon R. McQuade, Bernie V. McInerney, Nigel K. Stepto found that the provision of N-acetylcysteine (NAC) before a HIIT cycling exercise (6x5min HIIE bouts at 82 % PPO (316 ± 40 W) ) separated by 1min at 100W, then after 2min recovery at 100W) elevated the fat oxidation yet only during the last two bouts by 150%. It also reduced the makers of lipid oxidation (these are cell lipids not stored fat) and lactate levels after the time trial. However, the mean EMG activity was -7% and the mean power output 4.9% lower during the NAC trial.
  
  Now, whether that's a good or bad thing actually depends on your goals. If you are glucose tolerant and train to burn fat, it's a good thing. If you want to empty your glycogen stores to promote GLUT-4 or are a competing athlete whose main interest is maximal performance, though the changes would be detrimental.

• Exercise training vs. dieting - anti- vs. pro-inflammation (Auerbach. 2013) In a soon-to-be-published paper in the American journal of physiology. Regulatory, integrative and comparative physiology scientists from the University of Copenhagen report that contrary to their own expectations, the adherence to an endurance exercise program that would burn ~600kcal /day (LISS training of 65% of the heart rate reserve) that was interspersed by 3-4 days of high intensity workouts at 85% of the heart rate reserve ...
  

  "[...] increased the number of anti-inflammatory CD163⁺ macrophages (from 12.7 [2.1] (mean [SE]) to 16.1 [3.1] CD163⁺ cells/100 adipocytes, P=0.013), whereas diet-induced weight loss tended to decrease CD68⁺ macrophages in subcutaneous abdominal adipose tissue" (Auerbach. 2013)

  In that it is interesting to note that the most beneficial changes were observed in the group that compensated for the 600kcal extra energy expenditure per week.

  

  Figure 1: Effects of the 12 week diet + exercise / diet only / exercise only interventions on the body composition of caucasian overweight men aged 20-40 yrs w/ body fat >25% (Auerbach. 2013)

  Compared to the exercise + baseline diet and diet only (-600kcal energy reduction) group, they had a highly significant decrease in the TNF-alpha in the femoral adipose tissue ended and the greatest increase in anti-inflammatory CD163⁺ macrophage. 

• Carnitine rescues fast-twitch glycolytic macrofibers in a rodent study (Couturier. 2013) According to a recently published paper in Nutrition & Metabolism, the provision of carnitine as part of the diet did prevent the type-II-diabetes-induced transition of glycolytic to oxidative muscle fibers in obese Zucker rats.
  
  Now while you can never be sure if things that happen in a rodent model will also happen in man, it is not totally unlikely that these effects could be observed in human beings as well.
  

  

  Carnitine to prevent sugary fat gain

  "The results demonstrate that carnitine supplementation to obese Zucker a rat counteracts the obesity-induced muscle fiber transition and restores the muscle oxidative metabolic phenotype. Carnitine supplementation is supposed to be beneficial for the treatment of elevated levels of plasma lipids during obesity or diabetes. " (Couturier. 2013)

  The corresponding human equivalent dose to the 3g/kg of carnitine in the rodent chow would be would be roughly 16mg/kg or something between 1-2g per day for an adult human being (learn how to calculate HEDs). This is actually not really much and may well be worth a try, assuming that your own or your relatives' glucose burning, weight lifting musculature is endangered by diabetes.  

That's it for the short news!

In case you still have enough glycogen left in any of your major "tanks", or, alternatively, are depleted enough to have your body produce tons of ketones to fuel your brain for another 3-5 minutes you may yet want to take a brief look at the latest SuppVersity Facebook News...

• 

  With the relation of fish oil to prostate cancer (see facebook news) being based on high serum levels, I suggest you (re-)read this post about why fish oil supplements may fail to increase tissue levels, of way which previous studies have shown that they may protect against prostate cancer (read more).

  High or low fat for blood lipids? - Recent meta-analysis says: "The jury is still out there." The same appears to be the case for the type of fat, by the way | read more...
• Fish oil is bad for your prostate! - That's at least what the latest spin-off of the SELECT study (the one with selenium and vitamin E, you know?) says | read more...
• Green tea, butter and bread - Neither the most nutritious, nor the most yummy breakfast one can thing of, but way better for your triglyceride levels than water, butter and bread | learn why....
• Fat gains with saturated fats? Not if you pick the right ones - Study identifies interestification of saturated fat as a main determinant of its obesogenic effect. Regular palm oil, for example leads to lower fat gains than soy oil | read more...

... before you either eat, train sleep or have fun on the best day of the weekend: Saturday! ... What's so special about Saturday? Well easy, you can sleep late, shop, work out, party and whatever you like and sleep all the exertions and occasional "spiritual diversions" off on Sunday ;-)


References:

• Acordi da Silva et al. Effects of taurine supplementation following eccentric exercise in young adults. Applied Physiology, Nutrition, and Metabolism. 2013
• Auerbach P, Nordby P, Bendtsen LQ, Mehlsen JL, Basnet SK, Vestergaard H, Ploug T, Stallknecht BM. Differential effects of endurance training and weight loss on plasma adiponectin multimers and adipose tissue macrophages in younger, moderately overweight men. Am J Physiol Regul Integr Comp Physiol. 2013 Jul 10. [Epub ahead of print]
• Couturier A, Ringseis R, Mooren FC, Krüger K, Most E, Eder K. Carnitine supplementation to obese Zucker rats prevents obesity-induced type II to type I muscle fiber transition and favors an oxidative phenotype of skeletal muscle. Nutr Metab (Lond). 2013 Jul 10;10(1):48.
• Trewin et al. N-acetylcysteine alters substrate metabolism during high-intensity cycle exercise in well-trained humans. Applied Physiology, Nutrition, and Metabolism. 2013
• Gleeson, M. Biochemestry of Exercise in Maughan, Ronald J., ed. The Encyclopaedia of Sports Medicine An IOC Medical Commission Publication, Nutrition in Sport. Vol. 7. Wiley.com. 2008.

Science Round-Up Seconds: NAC Reduces Inflammation, Muscle Injury & Cytokine Expression, but Impairs Anabolic Signaling, Satellite Cell Activity and Recovery

Inflammatory cytokines won't build muscle, but without them your body won't notice that it's time to adapt.

As a SuppVersity student and listener of the SuppVersity Science Round-Up on Super Human Radio, you will be well aware of the fact that "inflammation" is a pretty loosely - or, I should say, lousily - defined and largely misunderstood term. What most people think of, when they hear the word has little to do with our bodies cytokine reponse (which is "inflammation") and is all about oxidative stress, which is one of the triggers of the release of cytokine. This is a process of which you've already learned that it plays a vitally important role in our bodies' ability to appropriately react to the wear and tear each and every of our cells is exposed to day by day, month by month and year by year. In fact, the misunderstood "inflammation" is a vital necessity to avoid the development of cancer. After all, it is the inflammatory response to the presence of degenerate cells that is what kills them before they can start to proliferate an turn into a systemic problem.

In this context, the feared "inflammatory" markers, IL-6 (interleukin 6) and TNF-alpha (tumor necrosis factor alpha) are of paramount importance as they are part of the singaling cascade that will have our bodies' own defenses target and cull the said degenerate cells before they become "immortal" cancer cells.

Inflammation and the adaptive response to exercise - the hormesis hypothesis

Figure 1: Health and longevity as a function of mitochondrial reactive oxygen species (ROS) formation (learn more)

That being said, previous studies in healthy human beings have yielded conflicting results as far as the effect of normal-to-large doses of exogenous anti-oxidants are concerned. According to scientists like Ristow and Schmeisser from the Department of Clinical Nutrition at the German Institute of Human Nutrition in Nuthetal, Germany, the suppression of the natural / normal cytokine response to the wear and tear of exercise will blunt the hormetic (=everything that does not kill you makes you stronger) response of which they believe that it drives the beneficial effects of working out.

Yet, while there are studies that would confirm this notion, the available data is by no means conclusive and a recent close review of the literature reveals that the consumption of "passive" anti-oxidants (e.g. vitamin C, vitamin E & co, i.e. molecules that simply eradicate reactive oxygen species and will thus blunt not regulate the cytokine response) appears to have either no, or detrimental effects in younger, relatively healthy individuals, the majority of the currently available data in older and sick individuals points to benefits of modest anti-oxidant supplementation.

We know that we know too little...

In short, we are still in the limbo as far as the "to use or not to use antioxidant supplements" question is concerned. Against that background I am grateful for every study that may help us solve this "mystery" and further our understanding of when a perfectly healthy and normal physiological response becomes pathologic and whether, when and for whom the use of specific anti-oxidants may be beneficial.

If you want to hear and learn more about the study at hand, the effects of other anti-oxidants and NSAIDs, and have not had the chance to listen live to yesterday's installment of the Science Round-Up on the Super Human Radio Network I suggest you download the show before you go on reading (click here to download).

Now without taking away too much in advance the latest of theses studies, I can already tell you that the actual outcomes of the latest study from the Democritus University of Thrace in Komotini and a couple of other European institutes, could confirm the scientists' hypotheses that the use of NAC [N-acetyl-cysteine; one of the most potent anti-oxidant supplements] during an 8-day eccentric and thus particularly "muscle damaging" exercise intervention would lead to an increase in GSH availability that would [...]

• ameliorate skeletal muscle performance by reducing inflammatory processes and exercise-induced muscle injury 
• attenuate intracellular redox dependent signaling pathways

and does nevertheless raise the question whether this really is something the average, healthy athlete should be looking for.

Figure 2: Allegedly beneficial effects on the irrelevant markers of inflammation, negative effects on what you are training for - the exercise induced increase in muscle protein synthesis (as evidenced by AKT, mTOR) and satellite cell incorporation (as evidenced by MyoD; adapted from Michailidis. 2013)

If you take look at the data I plotted in figure 2 it is quite obvious that the beneficial effects the participants, 10 healthy male volunteers with at least one month of thrice weekly strength training experience who consumed 20 mg NAC/kg per day (spread in three equal doses) dissolved in a 500-mL drink that contained water (375 mL), a sugar-free cordial (125 mL), and a 2-g low-calorie glucose/dextrose powder to improve palatability, experienced, namely ...

• an attenuation of the exercise induced elevation of inflammatory markers of muscle damage (creatine kinase activity, C-reactive protein, proinflammatory cytokines), nuclear factorkB phosphorylation, and 
• an amelioration of the damage-induced strength decrease during the first 2 d of recovery,

were  accompanied by a blunted increase in phosphorylation of protein kinase B, mammalian target of rapamycin (mTOR), p70 ribosomal S6 kinase, ribosomal protein S6, and mitogenactivated protein kinase p38 (MAPK) 2d and 8days after the workout.

Now, you could well argue that this is simply a result of less damage, right?

Was it mitohormesis that helped Walter Breuning live to the biblical age of 114 (learn more)?

It would at least seem logical that reductions in structural damage and (potentially - this was not accessed) loss of muscle protein in response to the 300 eccentric unilateral repetitions (20 sets, 15 repetitions/set, 30-s rest between sets) of leg extensions at a speed of 30°/s, the participants performed on an Isoforce (TUR Gmbh) isokinetic dynamometer, would entail a recuduction in compensatory protein synthetic response. In other words, with less damage the same amount of protein (re)synthesis that's insufficient to produce gains or at least restore the baseline protein content in the non-supplemented group could  well suffice to do just that in the NAC group.

(Unfortunately?) this is nothing but a neat hypothesis - one that is not supported by the results of the study at hand, in which the scientists also observed

• a blunted increase in myogenic (=satellite cell replenishing / recruiting and muscle repairing and building) factors and
• the failure to fully recover from eccentric exercise

in the supplement group. It goes without saying that the opposite should have been the case, if our neat hypothesis in defense of NAC supplementation as a means to increase athletic performance and muscle gains by buffering the exercise induced muscle damage, were true.

It's only logical that you wouldn't want to suppress the reactive oxygen species (green-yellow) too much, as their presence in the vicinity of muscle cells (blue) is not just a "stressor", but also important signal that will trigger and regulate the adaptive response to exercise (learn more)

Bottom line: NAC turns out to be an excellent example that well-meant interventions with outcomes that have classically been associated with positive health / performance effects (reduced CK, increased GSH, etc.) do not necessarily translate into beneficial real-world effects. In fact, the long(er)-term consequences of the attenuated cytokine (I am deliberately not using the term "inflammatory", here) response to exercise will probably be rather detrimental than beneficial for the more experienced healthy (young) physical culturist.

For other individuals which have to re-establish a healthy baseline level of glutathione and cut back on non-exercise induced oxidative damage (elderly, obese, diabetics, etc.), it may yet well be the other way around. These people may only be able to benefit from the exercise-induced cytokine response, if it is not drowned by an over-abundant amount of "pro-inflammatory" cytokines from other stressors.

References:

• Michailidis Y, Karagounis LG, Terzis G, Jamurtas AZ, Spengos K, Tsoukas D, Chatzinikolaou A, Mandalidis D, Stefanetti RJ, Papassotiriou I, Athanasopoulos S, Hawley JA, Russell AP, Fatouros IG. Thiol-based antioxidant supplementation alters human skeletal muscle signaling and attenuates its inflammatory response and recovery after intense eccentric exercise. Am J Clin Nutr. 2013 May 29.

Mitohormesis - Suffocated Mitochondria Live Longer: Scientists Probe Longevity-Effect of Low-Level Stressors.

Image 1: Walter Breuning died in April 2011at the biblical age of 114! And you bet that a man who has seen two world wars has had his share of mitohormetic stress in his life.

As a diligent reader of the SuppVersity you will be familiar with the work of S. Schmeisser and M. Ristow from the Department of Human Nutrition at the University of Jena, here in good old Germany (where not everyone eats Sauerkraut und Weisswurst, even now that the Oktoberfest is in full swing). In previous publications, the scientists have (at least in my mind conclusively) argued against the publicly accepted free-radical hypothesis of aging, which implies that the presence of free radicals is one of the fundamental mechanisms of aging. Now, a few month after the publication of their last review back in May 2011, they are presenting the latest results from their own lab in a paper that is going to be published in the October issue of Hormone and Metabolic Research (Schmeisser. 2011).

Want to live longer? Then you better put another log on the fire

Schmeisser, Zarse, and Ristow used lonidamine (LND), a indazole-3-carboxylic acid derivate, to inhibit cellular respiration in the infamous round-worm (Caenorhabditis elegans) model for aging processes (for a review on the pharmacology, biochemistry and toxicology of lonidamine see Silvestrini. 2008). In essence, they thusly made it more difficult for the cells to "breath", which as you may probably imagine, is a major stressor, which will inevitably increase the formation of purportedly dangerous free radicals (ROS) and should thus increase the aging process, if... yes, if there was any truth to the nonsensical idea that you better sit there, don't eat, don't drink, don't move - in essence - don't live to avoid any potential ROS formation, if you want to extend your lifespan... I guess, you as a self-educated SuppVersity reader won't be surprised that the roundworms did not only survive the "torture" (of life), but - after an initial mitohormetic response, i.e. an adaptational response to the the scientists' effort to suffocate their mitochondria (the initial reduction in oxygen consumption was -37 %!) - thrived on the purportedly life-shortening inhibitor of mitochondrial respiration!

Figure 1: Lifespan of C. elegans treated with 5µM lonidamine, n-acetyl-L-cysteine (NAC) or both (data calculated based on (Schmeisser. 2011)

As you can see in figure 1, the "pro-oxidant" treatment with lonidamine, of which Schmeisser's, Zarse's and Ristow's data shows that it increased respiration and thus mitochodrial ROS formation, increased both median as well as maximal life-expectancy of the nematodes (roundworms) by ~8% - an increase with statistical significance, as the p-value of p<0.001 (= chances that the increased lifespan observed in the study is just coincidence are <0.1%). The latter cannot be said of either the slight increase in maximal lifespan nor the slight decrease in median lifespan in the group of nematodes that was treaded with n-acetyl-L-cysteine (p=0.17; non-significant) or a combination of the anti-oxidant sulfur-amino acid and lonidamine (p=0.95; absolutely non-significant; cf. figure 1).

These observations may be considered further experimental "evidence" for Schmeisser's and Ristow's previously formulated mitohormesis theory ("evidence" in the sense that the results do not falsify their hypothesis - they do yet falsify the ROS hypothesis of aging). A theory that refutes the idea that the aging process is driven by reactive oxygen species and emphasizes (mitochondrial) adaptation processes to (external) stressors that strengthen, not weaken the organism in the long-run - or as the scientists phrase it:

[...] the induction of endogenous defense mechanisms as a secondary response to a stressful condition is assumed to contribute to longevity [...] a lifetime low dose oxidative stress with a subsequent secondary induction of defense mechanisms could delay the aging process

It is thus the interplay of manageable stress and metabolic adaptation which extends life and not an overall reduction of reactive oxygen species, as the vendors of some "super-potent" anti-oxidants would have you believe. What is still missing though, is a tool which would help us to identify the critical point, where the endogenous adaptation processes cannot keep pace with ever-increasing (mainly) exogenous stressors... in case any scientist finds an answer, I guess you will soon be able to download the respective app on your shiny new iPhone - I just hope that this app will account for the significantly (!) decreased glucose metabolism the iPhone itself will induce in the temporoparietal junction and anterior temporal lobe of the right hemisphere of your brain within less than 30 minutes (Kwon. 2011), as well.

N-Acetylcysteine Hampers Adaptive Response To Exercise. 50% Reduction in JNK Phosphorylation Entail Reduced Expression of Genes Involved in Cell Proliferation, Apoptosis, Inflammation and DNA Repair.

Image 1: The "beneficial" bad guys under
the microscope: Reactive oxygen species
(green-yellow) within endosomes
of human smooth muscle cells
(Circulation Research. 09/2007)

If you listened to my dissertation on the sulfur-amino acids on Carl Lenore's Super Human Radio (cf. shownotes), you will be aware that I was and still am quite skeptical as far as the touted beneficial effects of n-acetylcysteine (NAC) supplementation on exercise performance are concerned. A very recent study that has been conducted by a team of Australian scientists from Deakin and Victoria University in Melbourne appears to warrant this skepticism.

In a 2006 study (McKennah. 2006) the same group had found that N-acetylcysteine can attenuate the decline in muscle Na+,K+-pump activity and thus delay fatigue during prolonged exercise in humans. But even then, the data on real-world and long-term benefits of n-acetylcysteine supplementation was conflictive and the authors' conclusion that NAC exerted it's effect mainly via the suppression of ROS (reactive oxygen species) generation, prompted questions on whether the suppression of exercise-induced ROS-generation would have any downstream effects on the hormetic (=positive adaptation / strengthening reaction after an insult) response scientists suspect to be the major driving force of the beneficial effects of exercise on perfmormance, as well as general and metablic health.

Illustration 1: Hypothetical dose-response curve of the hormetic response to reactive oxygen species inducing exercise (x-axis, arbitrary units); positive units on the y-axis indicate beneficial, negative units negative effects.

Indeed, a 2009 study by a group of scientists from the University of Jena (Ristow. 2009) was able to show that administration of an anti-oxidant supplement that contained 1,000mg vitamin C and 400 IU of vitamin E prevented the health-promoting effects of exercise on in trained, as well as untrained subjects.

Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.

In view of the latter results, the major news here is neither that an N-acetylcysteine infusion before a 45min. cylcing trial at 71% of the individual VO2max that was followed by a bout of all out sprinting to fatique partially blocked the release of reactive oxygen species in the eight male subjects (age, 27.1±5.6 years; height, 180.3±5.4 cm; body mass, 76.7±10.9 kg), nor the related prolongation in time to fatigue the scientists observed. What is new, however, is the data Petersen et al. obtained from sophisticated analyses of the activation of signaling pathways and genes, which have been implicated in exercise adaptation in human skeletal muscle (Petersen. 2011).

[...] NAC infusion blocked the exercise-induced increase in JNK phosphorylation, but not ERK1/2, or p38 MAPK.  Nuclear factor-κB p65 phosphorylation was unaffected by exercise; however it was reduced in NAC at fatigue by 14% (P&amp;amp;amp;amp;lt;0.05) compared to pre-infusion.

This is an important finding, in so far, as it goes to show that the induction of JNK phosphorylation by exercise is ROS-dependent. Now, a -49% reduction in phosphorylation of JNK, a protein that has been shown to be activated as a consequence of strenuous aerobic and/or strength training, would not be a bad thing, if its activation would not play a significant role in the regulation of genes "involved in cell proliferation, apoptosis, inflammation and DNA repair (Karin and Gallagher. 2005) and thus [...] exercise adaptation."

It is difficult to say how the results of this short term study with intravenous n-acetylcysteine will translate into athletic practice. The (over-)consumption of large doses >>1-2g of oral NAC to facilitate exercise recovery, as it has been implicated by some of the advocates of the acetylated version of the sulfur-amino-acid cysteine, by all means, seems to be counter-indicated, as another dreaded foe, exercise-induced reactive oxygen specimen (ROS), eventually exhibits its complementary, hormetic face. The real challenge is thus not extinguish the fire, but to keep it burning at an optimal rate, or, metaphorically speaking, to generate and/or suppress ROS in a way which facilitates a precision landing on the maximum of the graph in illustration 1 ;-)

Amino Acids for Super Humans. Part IV: Purported Ergogenics - Beta Alanine, Carnitine, Glutamine

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Amino Acids for Super Humans. Part IV
Purported Ergogenics - Beta Alanine, Carnitine, Glutamine

In the fourth installment of the show, we are going to look at three of those amino acids everyone interested in fitness and body building knows: Beta Alanine, Carnitine and Glutamine. Will the increase performance, fat loss and muscle gains, as some supplement companies would have it, or will they mostly cost your hard earned money or even make you sick? Tune in live @ 1pm ET and learn more!

Show Notes: Amino Acids for Super Humans. Part III - Sulfur, More Than Just Rotten Eggs.

Amino Acids for Super Humans. Part III

Sulfur, More Than Just Rotten Eggs

Episode available for download, now!

notice! this are 100% uncorrected show notes not originally intended for publication

In this episode we are going to tackle:

• methionine (essential amino acid, EAA)
• cysteine (conditionally essential amino acid)
• n-acetyl cysteine (acetylated variety of cysteine, not found in food sources)
• taurine (non-essential amino acid)

Amino Acids for Super Humans. Part III - Sulfur, More Than Just Rotten Eggs.

This relevant for all of you - regardless of whether you can or cannot spare the time: Tune in live and listen to me @ Carl Lenore's Super Human Radio to learn that amino acids are far more than just the building blocks of the proteins of your body...

Listen live to SHR @ 12:00PM ET

Amino Acids for Super Humans. Part III
Sulfur, More Than Just Rotten Eggs
update: Episode available for download, now!

In the third installment of the show, we are going to look at the commonly overlooked. yet vitally important sulfur-containing amino acid methionine, its "children" and "grand children", cysteine, n-acetyl-cysteine (NAC) and the purported "cell volumizer" taurine.

As usual, I will do my best to provide relevant examples and relate the theory to practical advice. The magic of individual amino acids will be tackled in the shows to come.

update: Episode available for download, now!

NAC + Zinc + Selen = Silver Bullett Against Mercury Poisoning

Mercury certainly is among the most dangerous and, at the same time, most ubiquitous heavy metals, we are exposed to. In a recent article (thanks to Dominique for raising my awareness of its publication) strength coach Charles Poliquin references a 2010 study from Michigan State (Wirth. 2010) :

Looking at several well-designed studies, they determined that even low exposures from cadmium, lead and mercury had an impact on semen quality and reproductive hormone levels in men.

As far as solutions to this problem are concerned, Polliquin refers somewhat dubiously to "a specific herbal combination" of "andrographis paniculata, zinc citrate, humulus lupulus, and curcuma longa" without providing scientific evidence for why he thinks this specific formula would work (guess what, Charles sells it ;-). Chances would have it, though, that Joshi et al., in a very recent study (Joshi. 2011, still ahead of print) report the beneficial effects of another, from my perspective, probably even more potent combination of nutrients/antioxidants in experimentally induced mercury poisoning:

Exposure to DMM [dimethylmercury] caused significant alterations in cytochrome P450 (CYP) activity, microsomal lipid peroxidation, and proteins [in rats]. Activities of transaminases (aspartate aminotransferase/alanine aminotransferase), alkaline phosphatase, and lactate dehydrogenase in serum, as well as activities of CYP enzymes aniline hydroxylase (AH), amidopyrine-N-demethylase (AND) in liver microsomes and activities of acid phosphatase, alkaline phosphatase, glucose-6-phophatase, and succinic dehydrogenase in the liver and kidney, were significantly altered after DMM administration. DMM exposure also induced severe hepato-renal alterations at the histopathological level. NAC, along with Zn and Se, dramatically reversed the alterations in all of the variables more toward control.

Actually these results do not come as a surprise, as all three of these nutrients/antioxidants are well-known for their beneficial effects on (liver) enzyme activity and thus heavy metal clearance. Those of you, who read Tim Ferris' book The 4 Hour Body may also remember that his Brazil nut consumption (he ate them for their high selenium content, 1 ounce contains 544µg, i.e. 780% DV) along with other nutritional changes tripled his testosterone levels from low normal levels to the upper quartile of the range. In that, it is of secondary importance whether this was a mercury related effect, or not, since an increase in the detoxification abilities of the liver, as it was achieved in the study by twice a week supplementation with NAC (360mg/kg; human equivalent dose [HED] ~ 52mg/kg)  + Zn (130mg(kg; HED ~ 26mg/kg) + Se 0.5mg/kg; HED ~0.08mg/kg), will benefit the hormonal millieu via multiple pathways (increased estrogen clearance being one of them).

A word of caution: I advice against using the dosing scheme applied in the study, i.e. twice a week mega-dosing of supplements. Spread across a whole week, the human equivalent doses (for an 80kg human being) would equal roughly 600mg NAC, 300mg Zinc and 1mg* Selenium per day, which - apart from the exorbitant amount of zinc (I would not take more than 100-150mg/day even for short term interventions) - constitutes a quite reasonable nutrient stack for shorter detox protocols (4-6 weeks) for mercury, cadmium (cf. eg. Said. 2010) and other heavy metals with an increase in testosterone being one of the possible positive "side effects".

*Note on selenium toxicity: Rumors have it that selenium is toxic even at doses of >400µg. Most of these reports yet turned out to be based on anecdotal evidence from people who poisoned themselves with supplements that contained up to 200x the labeled dose (e.g. >40mg! selenium in MacFarquhar. 2010). It is thus very unfortunate that current data on the ‘Lowest Adverse Effect Level’ (LOAEL) is lacking. A 1989 study by Yang et al. give1.5mg/day as a threshold beyond which longterm supplementation may produce adverse side effects. And though this is below the 1g derived from the results of the rat study, I recommend to better err on the side of caution and to stick to max. 200-400µg supplemental selenium + a handfull of Brazil nuts from time to time as part of a safe antioxidant supplement stack.

Reactive Oxygen Specimen (ROS) Trigger Muscle Hypertrophy via IGF-1 Signaling

I have touched on the "usefulness" of oxidation, only yesterday. Now, a very recent study appears to confirm the notion that a controlled amount of inflammation is necessary in order to achieve metabolic and muscular adaptations.

Figure 1: Eesult of the quantitative analysis of myotube diameter after IGF-I and NAC treatment (Handayaningsih. 2011)

Scientists from Division of Diabetes and Endocrinology and Division of Cellular and Molecular Medicine at the Kobe University Graduate School of Medicine published a paper (Handayaningsih. 2011) describing an investigation into the role of Reactive Oxygen Specimen (ROS) in the IGF1-signaling pathway. In this study N-Acetyl-Cystein (NAC), commonly used by recreational athletes as an "ergogenic" aid, blunted myocyte response to IGF1 and thus inhibited muscle hypertophy (cf. Figure 1):

While treatment with H2O2 significantly enhanced IGF-I-induced phosphorylation of the IGF-I receptor (IGF-IR), IGF-IR phosphorylation was markedly attenuated when cells were treated with antioxidants. The downstream signaling pathway, Akt-mTOR-p70S6K was subsequently down-regulated. Furthermore, thephosphorylationof FoxO1by IGF-I decreased concomitantly with the restoration of the expression of its target genes, Atrogin-1 and muscle RING finger 1, which are related to muscle atrophy.

Before you now go and flush all your vitamins and antioxidants down the toilette, you should consider that this is an in-vitro study with a narrow and limited ROS stimulation and not a large scale exercise supplementation study showing that the 500-1.000 mg of NAC you take on a daily basis will completely forestall muscle growth. If anything, it should remind you that excessive "inflammation" could be the "root of all evil" (cf. Super Human Radio), but excessive antioxidant supplementation certainly ain't a solution.

NAC Improves Markers of Oxidative Stress Induced by High Intensity Exercise

The word "anti-oxidant" has lost some of its glory within the past couple of years. In absence of overt deficiency, the real-world effects of super high doses of vitamins and other nutrients which have been found to exhibit anti-oxidant activities is negligible if not opposing to the originally intended effect. One of those anti-oxidants which may even produce adverse side effects at very high doses is N-acetyl-cysteine (NAC).
For athletes who expose their bodies to a high amount of oxidative damage, NAC may yet well be a candidate for the list of basic supplements you may want to consider to take. A recent study (Trevin. 2010) involving nine well-trained male cyclists (mean ± SD; 27 ± 6 years of age, VO2peak 69.4 ± 5.8 ml.kg−1.min−1) found that a NAC-loading protocoll consisting of 2 days on 100mg/kg NAC, followed by one day with two servings of 100mg/kg and another dose of 100mg/kg 1h before a 10 minute self-paced time trial, produced the following results:

Respiratory Exchange Ratio (RER) was decreased in the NAC condition throughout HIT exercise, and was significant at bouts 1 and 5 (p < 0.05) as shown in The Figure. Compared to placebo, NAC decreased blood lactate during TT and recovery (p < 0.05). Both pH (p < 0.01), and HCO3 (p <0.05) were reduced throughout exercise and recovery with NAC. In contrast NAC resulted in higher blood glucose concentration during HIT (p < 0.05). EMG median frequency of the vastus lateralis decreased in HIT bout 6 in the NAC condition (p < 0.05). No significant difference was observed in the total work performed in the 10-min TT (p = 0.16) .

So, while it had no direct effect on exercise performance, NAC did increase several performance and recovery related parameters and probably shifted the substrate metabolism from carbs to fats, thus leaving the athletes with a higher blood glucose concentration during and after their high intensity interval sessions.