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<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 ;-)