Friday, June 7, 2013

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.

  • 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.


  1. Thanks for remembering us overweight, pre-diabetic, old people in your last paragraph. If I can significantly slow sarcopenia via strength training and yet still increase my glutathione levels with some NAC, I'll be quite satisfied.

    1. It could also be a problem of the dosage (out of my head the few actual beneficial studies I remember on NAC in "normal" individuals - previously untrained though - were using "only" 800mg AND - this may also make a difference - taken at once)

      on the other side, as I wrote and said on the show - it appears as if the older you get the more you benefit, because the tighter the margin between hormesis and damage will become

  2. Again and again, the same old story. However, recently:
    we conclude that there is no evidence that antioxidant vitamins interfere with the adaptive responses to endurance exercise training.

    The whole reasoning that you bring here could be equally used in other direction. I mean, its only logical that there is certain level of exposure (AFAIK small one) after which hormesis stops and real damage begins.

    Its also beyond understanding how people tend to concentrate on this very issue and ignore all or most of the other benefits of "antioxidants" - books are written about NAC and its positive effects on health, and libraries on vitamin C.

  3. However, adaptation is also well known element of progress and to have it, u need stressor. The fact that antioxidants reduce stress could indeed prevent such progress. Unfortunately, antioxidants are chemicals that do many things and are not doing the things you want them to or don't. Vitamins are part of millions of reactions in a body, and underlining just one type of reaction doesn't make much sense unless in academic settings.

    So the real question is not if it happens or not, but if it really happens, is this fact alone worse then all other things combined. I am sure that the answer will be far from that... judging from the extraordinary high number of diseases that results from not even deficiency, but marginal sufficiency of all micronutrients.

    1. while I tend to agree on the last point, I strongly disagree on the need of supplementation with the standard "anti-oxidants" in copious amounts - but we had this discussion numerous times ;-)

      and on a side note the level of vitamin C (your favorite) will increase in muscle in the absence of supplementation, just in response to exercise =>

    2. I think there's a big difference between the notion of 'deficiency' and 'mega-dosing' (such as vit c./e at 1000mg/400iu). I don't think that anyone would say to avoid them, but the 'positives' of taking more, in the context of performance, seem fairly baseless.

    3. 2 Anonymous
      Performance is an issue for minority. Health is issue for majority.

      2 Adel
      C will increase as GLUT4 is increased, simple as that. GLUTX transports both DHAA and glucose. In the inflamatory state after the exercise there will be a lot of DHAA around muscles. Its expected. The C has to come from somewhere -> since we don't produce it, something else suffers.

  4. NAC will supply GSH, GSH will supply GSSG, and NAC supplementation does not reduce GSSG to GSH, that is still subject to metabolic controls (glucose-6-phosphatase and NADPH from memory). That may be why there is a limit to any negative effects of NAC, because oxidative tone is only ever shifting slightly, and because the GSSG also has benefits, restoring that oxidative tone by generating NADP+?

    1. that is an interesting hypothesis, but I did not want to imply that taking even more NAC will make things even worse, in the first place. Even the extrapolation from this population to others is somewhat sketchy to extend that to higher amounts would thus not make much sense

  5. When did they take the NAC..? You should your high consert. Supp. Away from training..or at least after training. Then you should get the benefits with muscle gain. Or what is your take on ths sir Andro..?

    1. that is a nice hypothesis, of which I know that a special "friend" of mine who is usually unwilling (or unable) to participate in anything you could call a discussion, because he thinks too highly of himself to be even bother with the opinion of ordinary mortals... be that as it may, I am not aware of any scientific evidence to support that time of the day will matter. Once a week vs. every day could - but time of the day? Questionable.

  6. Great site! I am loving it!! Will be back later to read some more.looking for more updates.

  7. This comment has been removed by the author.

  8. Searched for this page after spotting a new "altitude training" supplement: Basically NAC + B12 and a few other things. Study:

    1. where is the "study" - a study is something that is published in a peer-reviewed scientific journal - THIS is a marketing piece - and trust me it just takes good writing skills, some research and a little cherry picking to have people buy horse manure, because "science says its good for you"

  9. very useful and informative article.Will come back for some more!!! :D

  10. exercise is actually any kind of bodily
    task which improves or maybe preserves beauty
    health and fitness and also entire health and wellness.It truly is performed with
    regard to a variety of motives including fortifying muscle tissue and the honing
    running knowledge, weight loss or even preservation, along with for the purpose
    of pleasure. Medical services usually call exercise .

  11. Good Doctor, will you please write a post addressing the narrow question of what doses and timings of green tea, cocoa, and resveratrol might interfere with muscular hypertrophy? Bits of the answer are in various of your other posts, but a summary would be useful. Specifically, I used to take every day before breakfast, about 350 mg of EGCG with one cup of green tea, a tablespoon of raw cocoa, and 250 mg of resveratrol. I waited 30-60 minutes before breakfast, then started hypertrophy workout 60 minutes after breakfast. But for fear of all those reducing "inflammation," I'm now taking those only on my exercise rest day--24 to 48 hours after last hypertrophy workout, and 24 hours before the next one. I want the vascular and other benefits of those supplements, but want to minimize interference with hypertrophy.