Research Update: Do NSAIDs Augment or Impair Exercise Induced Hypertrophy & Strength Gains in Young and Old?

Are you young and healthy? Then, high-dose NSAIDs may ruin your quad-gainz.

If you browse the SuppVersity Archive, you will find that NSAIDs, i.e. Non-Steroid(=not based on cortisone)-Anti-inflammatory-Drugs like aspirin, celecoxib, diclofenac, ibuprofen, or indomethacin, are not as bad as the bros in the locker-room may have told you.

In fact, a relatively recent study by Mackey et al. (2016) observed beneficial effects on muscle repair in young men. And an even more positive image of NSAIDs emerges if you read Trappe et al.'s 2016 study in which they observed significant increases in muscle gains in older trainees.
In Schoenfeld's 2012 meta-analysis the three human trials, investigating the effects of NSAIDs on skeletal muscle hypertrophy that were available at that time seem to confirm the notion that the use of the prostaglandin-blocking COX-enzyme inhibitors won't impair your gains: while two of the study produced a null result (Krentz 2008; Petersen 2011), the other one, once more a study by Trappe et al. (2011), recorded a significant increase in muscle hypertrophy in the elderly subjects of the study.

Figure 1: In their 2011 study, Trappe et al. observed significant (and in relative terms identical) increases in skeletal muscle hypertrophy when they examined the influence of acetaminophen (no NSAID) or ibuprofen (NSAID) consumption on muscle mass and strength during 12 wk of knee extensor progressive resistance exercise training in older adults.

You probably already noticed that I've italicized all attributes that describe the age of the subjects in my previous elaborations... well, that's not without reason: as pointed out in previous articles on NSAIDs the 2016 study by Mackey seems to be the exception to a rule that says "If you see benefits, you'll see them in older subjects".

What does the latest study on hypertrophy tell us?

If the previously phrased hypothesis (old = benefits, young = detriments) holds true, the result of the most recent investigation into the effects of NSAIDs on skeletal muscle hypertrophy which was conducted by Mats Lilja and colleagues from the Karolinska Institutet and the Swedish School of Sport and Health Sciences, in young, healthy men and women (aged 18-35 years) should yield a null or a negative result - and that's indeed what you can see in Figure 2.

Figure 2: The latest study by Lilja et al. observed a significant negative effect of high dose ibuprofen on hypertrophy.

When the scientists measured their subjects' muscle volume at the end of the 8-week training period, over the course of which subjects had ...

• consumed either ibuprofen (IBU; 1200 mg; n=15 - consumed in form of 3 separate 400mg doses at 8am, 2pm and 8pm) or a placebo, in this case acetylsalicylic acid aka aspirin (ASA; 75 mg; n=16 - consumed in the AM) at a dosage that was chosen low enough to assume that it won't mess with the study outcomes (if it did, it would only diminish the inter-group difference, so even if it did, the results of the study imply that NSAIDs impair muscle gains in young, healthy individuals), daily, and ...
• performed 20 leg workouts consisting of 4 × 7 maximal repetitions on a flywheel device (2 min rest) with one leg and 4 × 8–12 repetitions to failure a "weight stack" machine, of which I assume it was a leg extension device, with the other leg,

the scientists found similar increases in m. quadriceps volume with the flywheel and the leg-extension machine. What did differ, however, were the gains in the ASA = control and the treatment = IBU group: averaged across legs, the ASA (7.5%) group saw a significantly greater increase in muscle volume than the IBU (3.7%, group difference 34 cm³; P=0.029) group.
That's interesting because the subjects' strength gains didn't differ to the same extent. In fact, the leg extensions triggered (within the statistical margin of error) identical strength increases of 11-20% in both groups. The strength gains in response to the flywheel exercise, which allows for maximal voluntary force to be produced from the very first repetition, on the other hand, were "generally greater (interaction effects P<0.05) for ASA compared with IBU" (Lilja 2017).

A difference in training volume was observed neither in the study at hand nor in previous studies (where it was tested) - including those in older subjects that showed significant beneficial effects of NSAIDs on skeletal muscle hypertrophy such as Trappe et al. 2011 and 2016.

What's / what are the mechanism(s)? 

The problem about identifying the underlying mechanisms is that Lilja et al.'s extensive molecular analyses found only one statistically significant inter-group difference that could potentially explain the previously described detrimental effects of IBU on size and, to a lesser extent, strength gains: the sign. reduced mRNA expressions of IL-6 (P<0.0001) in response to high dose ibuprofen treatment.

Figure 3: Changes in IL-6 (left), COX1, COX2, PGF2-alpha, and p70S6K mRNA/protein expression (Lilja 2017).

That's a problem because it implies that the usual suspects, COX, prostaglandins, and the "protein synthesis trigger protein" p70S6K (all didn't change in the study at hand) cannot be blamed for the NSAID-induced reduction in skeletal muscle hypertrophy. In other words: it's (a) neither an inhibition of the pro-anabolic effects of PGF2α scientists as it has been observed repeatedly in the petri dish nor the previously observed in vivo reduction of p70S6K (downstream of mTOR) in the early hours following acute resistance exercise that would blunt the protein synthetic response.
While Lilja et al. speculate that they may have missed relevant signaling proteins or potential effects on satellite cells (note: a previous study shows that IBU expedites satellite cell recruitment, so that's very unlikely), I believe it's better to focus on the previously mentioned reduction in IL-6 - a reduction I would like to interpret as evidence of an overall reduced inflammatory/stress response, which could (a) impair the hormetic response to exercise in young individuals and thus explain the reduced hypertrophy in the study at hand (see Figure 2, 'NSAIDs in young individual'), and (2) reduce the already chronically elevated levels of of inflammation in aged muscles (Roubenoff 2003) to a tolerable level within the adaptation zone (see Figure 4, 'NSAIDs in old individuals') and could thus explain the increased hypertrophy Trappe et al. (2011) observed in their study in older individuals.

Figure 4: Illustration of the ways inflammation may trigger both, adaptation (hypertrophy and strength gains) and failed adaptation (catabolism and sarcopenia), depending on whether and to which degree it hits or misses the organism and age-dependent optimal degree of inflammation. This theory can explain why reducing the inflammatory load with NSAIDs will (1) reduce the gains in young individuals, who will end up with too little inflammation, and (2) improve it in elderly individuals, by reducing the degree of age-related chronic inflammation and bringing them back to the adaptation zone.

If this hypothesis is correct, an allegedly simplistic model of the interaction of NSAIDs with exercise-induced strength and size gains would describe them as tools that may hinder (young and healthy) or help (old or sick) you achieve "optimal" = hormetic levels of inflammation.
References:

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• Trappe, Todd A., et al. "Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis." American Journal of Physiology-Endocrinology and Metabolism 282.3 (2002): E551-E556.
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