IL-6 - True Muscle Builder or Just a Measure of Workout Intensity? Plus: If Testosterone Does Not Matter, Why Does the Androgen Receptor Density Make a Difference?

No matter how close we look, the influence of previous, i.e. GH, IGF-1 and testosterone, as well as novel, i.e. IL-6 and AR expression, potentially growth promoting suspects remains elusive.

SuppVersity readers know, there is more to "inflammation" than the average mass media article will make you believe. The same "bad cytokines" that will decrease your insulin sensitivity, make you sick and obese, when they leak from your "inflamed" beer belly, are actually the good guys, when they are released in response to a workout from the musculature. "Myo-", not "cytokines", that's how researchers refer to them (Pedersen. 2007); and their role in (exercise) metabolism and immunity is until now still not fully understood.

The results the scientists from the McMaster University probably won't add much to our understanding of the systemic effects of IL-6 and other myokines. What certainly do, though, is to support the notion that "inflammation" can have profound and very far-reaching effects on our physiology (learn more).

Does IL-6 build muscle?

The mere idea that IL-6, a molecule of which most people think that it was a good measure of how messed up your health actually is, could be a promoter, or at least a measure, of skeletal muscle growth in response to a workout sounds about as logical (or illogical, if you will) as the previously established fact that the allegedly anabolic hormones testosterone, IGF-1 and growth hormone don't show the slightest correlation with the exercise induced skeletal muscle growth (West. 2011; learn more in "Anabolic Workouts Revisited").

Figure 1: Relative increase in muscle CSA change for androgen receptor density and p70S6K expression (left) and individual correlation of endocrine changes and muscle CSA (right), data based on Mitchel. 2013)

What was to be expected, though, was the correlation between the skeletal muscle hypertrophy response to the 16 week / 4x per week exercise program the 23 previously untrained study participants had to endure, on the one hand, and the exercise induced increase in p70S6K, on the other hand. The signalling protein p70S6K is after all something like the "protein pump"-gauge in the mTOR cascade.

Strength training can increase the androgen receptor density

Less well-known, but also not really new is another observation Mitchel et al. made: The resistance training lead to an allegedly subject specific and overall insignificant increase in the density (number per area unit) of androgen receptors; and though the overall increase may not have been statistical significant, the correlation of the the increase in androgen receptor density and the lean muscle gains of the subjects was.

New myonuclei (blue) are necessary to keep growing (learn more)

What about the muscle structure? What I am missing in this study is a measure of the myonuclei and domain sizes. We know that inflammation plays a major role in the restructuring process of the musculature that's necessary to maintain myonuclear domain size and thus the capacity for muscle protein synthesis (Bamman. 2001). It does furthermore seem likely that the any increase in myonuclei number would go hand in hand with increases in the number of androgen receptors. The corresponding data could thus help us to answer some of the questions we still have about the immediate (mTOR) and the chronic (endocrine and immune) contributions to skeletal muscle hypertrophy.

Similar effects on the androgen receptor density have been described by Willoughby & Taylor in 2004, already. In the pertinent study from the Baylor University, this increase did yet go hand in hand with increases in total testosterone and the free androgen index, of which the authors say that they were brought about by persistent increases in testosterone - increases in testosterone that were not observed in the more recent study by Cameron Mitchel, where the testosterone levels dropped (albeit non significantly) in response to the 2x2 upper-/lower-body split training.

"Our study corroborates previous findings that mean AR protein expression was not increased following resistance training; however, the response had marked heterogeneity, with some subjects showing a marked (1.5 - 2.5 fold) increase in AR protein content [...] Despite no statistically significant change in AR receptor protein content, there was a correlation between AR protein content with fibre hypertrophy. Our results suggest that changes in AR content may be part of a muscle-specific response present to a greater degree in responders and responsible for some (~25%) of the variation in muscle fibre hypertrophy." (Mitchel. 2013)

With regard to the correlation (I want to emphasis that we don't have enough evidence to do anything, but speculate about causative effects, here), it may be worth mentioning that the statistical significant association between androgen receptor density and the changes in muscle cross-sectional area was more pronounced in the "strength type" fast twitch (type II) than in the "endurance type" slow twich muscle fibers (0.6, p = 0.002 vs. 0.47, p= 0.023).

For IL-6, on the other hand,  it was the exact opposite. Unlike the number of androgen receptors per muscle area, the amount of interleukin 6 that was released or, as Mitchel et al. say, "filtered" from the muscle into the blood stream in response to the workout exerted a minimally more pronounced effect on the slow twitch "endurance type" fibers (type II).

So is IL-6 anabolic? It is counter-intuitive and would be premature to say that "IL-6 plays a causal role in skeletal muscle hypertrophy". This is particularly true in view of the fact that high baseline IL-6 levels that would be indicative of chronic vs. acute inflammation were "inversely correlated with fibre hypertrophy" and that IL-6 per se "is associated with both muscle protein breakdown and JAK/STAT signalling in satellite cells" (Mitchel. 2013).

Acutely (green circle) IL-6 will help build muscle, chronically it will make you sick (Muñoz-Cánoves. 2013).

It does thus appear to be more likely to assume that the increased IL-6 response is - just as the previously observed increase in cortisol in West et al. (2011), by the way - a marker of the workout induced strain, which does - in a non-overtraining scenario! - predict the adaptive response and thus the actual muscle gains.

The fact that the inclusion of IL-6 in a model prediction of the exercise induced hypertrophy response did not increase its accuracy would also point towards a corollary, not a causal involvement of a cytokine, the local (=in the muscle) production of which has also been implicated in the protective effect of exercise against insulin resistance, as well as increases in lipolysis and fatty acid oxidation (Pedersen. 2007).

In the end I have to admit that the study at hand does not really offer the material that would be necessary to formulate something like practical implications. What the results Mitchel et al. present in their paper can do is to reaffirm that skeletal muscle hypertrophy occurs in a(n at least) bi-phasic process with (1) an acute "inflammatory" phase where P70S6K (part of the mTOR cascade) determines and IL-6 (and thus inflammation) correlates with an increase in lean muscle mass and (2) a long-lasting "recovery" phase where the increase expression of androgen receptors could play an important role in the maintenance of the immediate gains in skeletal muscle protein. Your training should thus provide for both: An intense hypertrophy stimulus on the training days and lots of time and nutrients to recover on your off days.

References: 

• Bamman MM, Shipp JR, Jiang J, Gower BA, Hunter GR, Goodman A, McLafferty CL Jr, Urban RJ. Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans. Am J Physiol Endocrinol Metab. 2001 Mar;280(3):E383-90
• McKay BR, De Lisio M, Johnston AP, O'Reilly CE, Phillips SM, Tarnopolsky MA, Parise G. Association of interleukin-6 signalling with the muscle stem cell response following muscle-lengthening contractions in humans. PLoS One. 2009 Jun 24;4(6):e6027. 
• Mitchell CJ, Churchward-Venne TA, Bellamy L, Parise G, Baker SK, et al. Muscular and Systemic Correlates of Resistance TrainingInduced Muscle Hypertrophy. PLoS ONE. 2013; 8(10): e78636
• Muñoz-Cánoves P, Scheele C, Pedersen BK, Serrano AL. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J. 2013 Sep;280(17):4131-48. doi: 10.1111/febs.12338. Epub 2013 Jun 18.
• Pedersen BK, Akerström TC, Nielsen AR, Fischer CP. Role of myokines in exercise and metabolism. J Appl Physiol (1985). 2007 Sep;103(3):1093-8. Epub 2007 Mar 8. Review.
• West DW, Phillips SM. Associations of exercise-induced hormone profiles and gains in strength and hypertrophy in a large cohort after weight training. Eur J Appl Physiol. 2012 Jul;112(7):2693-702. doi: 10.1007/s00421-011-2246-z. Epub 2011 Nov 22.
• Willoughby DS, Taylor L. Effects of sequential bouts of resistance exercise on androgen receptor expression. Med Sci Sports Exerc. 2004 Sep;36(9):1499-506.