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.

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.