Tuesday, February 2, 2016

High Dose NSAID Boosts Muscle Gains in Elderly Men - 11% Increase in Type II Fiber Size, Type I Grew Only 'on' Tylenol

Are NSAIDs over-the-counter anabolics from the pharmacy next door?
Even though this is not the first SuppVersity article about the effects of NSAIDs or COX-inhibitors like Aspirin, Tylenol, Pain-Eze and co., I would like to highlight one again that the existing evidence suggests differential effects in young(er) vs. old(er) individuals, with the former seeing no or detrimental and the latter no or beneficial effects when using NSAIDs during resistance training regimen.

It is thus neither guaranteed, nor likely that a young man or woman would see the same 28% extra-increase in type I fiber and 11% extra-increase in type II fiber diameter, Trappe et al. describe in their soon-to-be-published paper in the journal of the Gerontological Society of America (Trappe. 2016).
The link to hormesis research is far from being straight-forward

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I do understand, though that the numbers still got your attention. Well, let's take a close look at how the researchers got to these impressive results. It all started with previous research that suggested that common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals.

Unfortunately, the results of the few studies we have, are conflicting (Schoenfeld. 2012; see Table 1) - with one showing benefits and two showing no effect at all. The purpose of Trappe's latest study was thus to (a) simply gather more evidence and (b) investigate the mechanism behind the changes that were observed in previous studies. Or, as the scientists put it "whether the underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers" (Trappe. 2016).
Table 1: Summary of human studies investigating the effect of nonsteroidal anti-inflammatory
drug consumption on muscle hypertrophy (Schoenfeld. 2012).
To this ends, the scientists obtained muscle biopsies from the vastus lateralis of healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years | compliance was monitored by researchers, when tablets were taken at the lab or camera when taken at home) during a standardized 12 weeks resistance training program (only the knee-extensor was trained - albeit on 3 days/week) the scientists describe as follows:
"All participants completed a progressive resistance exercise training program of bilateral knee extension that was designed to hypertrophy and strengthen the m. quadriceps femoris, using a protocol employed for several previous investigations in our laboratory. Each participant was scheduled for resistance training three times per week over the 12 weeks for a total of 36 sessions on an isotonic knee extension device (Cybex Eagle, Medway, MA). All sessions were supervised by a member of the research team. Each session was separated by at least 1 day and consisted of 5 minutes of light cycling (828E, Monark Exercise AB, Vansbro, Sweden), two sets of five knee extensions at a light weight, followed by three sets of 10 repetitions with 2 minutes of rest between sets. Training intensity was based on each individual’s one repetition maximum (1RM) and adjusted during the training based on each individual’s training session per formance and biweekly 1RM" (Trappe. 2016).
The compliance of the subjects of this double-blinded study is described as excellent. Therefore, we can assume that the significance of the results of the scientists' analysis of muscle samples that were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, β-hydroxyacyl-CoA-dehydrogenase) is high.
Figure 1: Pre-/post comparison on fiber (according to fiber type) and muscle size (Trappe. 2016).
Obviously, the most important results of these analysis have been mentioned before: While the type I fiber size did not change with training in the placebo group (304±590 μm²), it increased by a statistically significant and practically relevant 28% in the COX inhibitor group (1,388±760 μm²).
Schematic of the prostaglandin (PG) producing cyclooxygenase (COX) pathway and specific receptors that influence growth and atrophy in skeletal muscle (Trappe. 2013b).
How do COX inhibitors promote hypertrophy? As Trappe et al. point out "[e]vidence from the larger cohort suggests that the augmented muscle growth was primarily mediated by a reduction in intramuscular PGE2 and resultant PGE2 receptor downstream signaling effects (Standley. 2013; Trappe. 2013a,b). Specifically, the COX inhibitor appeared to reduce the negative effects of PGE2 on protein synthesis and degradation, working through established myokines and other cellular regulators of protein turnover. The myocellular findings from the current study suggest that these effects were more pronounced in the Type I fibers, possibly due to a more active PGE2/COX pathway in this fiber type" (Trappe. 2016).

In addition, the authors point out that previous evidence suggests an "additional mechanism for the COX inhibitor–induced supplemental growth, working through PGF2α receptor and protein synthesis upregulation" (Trappe. 2016; referring to Trappe. 2013a,b).
For the type II fibers, both groups recorded significant increases in fiber size. With "only" 26%, the gains of the subjects in the the placebo group (1,432±499 μm2, p < .05) were yet measurably lower than those in the COX inhibitor group whose vastus lateralis type II muscle fiber size increased by 37% (1,825±400 μm², p < .05). In view of the overall benefits the COX group saw, it is thus hardly surprising that the subjects consuming the COX inhibitor recorded significantly greater total muscle CSA gains (see Figure 1, right | note: only the total mass gain was sign. different between groups).
Figure 2: Change in fiber type–independent (A) and fiber type–specific (B) muscle capillarization from the beginning to the end of the 12-week resistance exercise training and drug interventions. CCEF = capillaries in contact with each fiber; CSA = cross-sectional area. *p < .05 vs pre. **p < .1 vs pre.
While enzyme activity (not shown in Figure 2) and capillarization were generally maintained in the placebo group, the capillary to fiber ratio of the subjects in the COX inhibitor group increased by an albeit only borderline significant 24% (p < .1). The citrate synthase activity, on the other hand, increased statistically significantly, but by "only" 18% (p < .05). These differential changes in citrate synthase (important for fat oxidation and endurance) and muscle capillarization further underline the beneficial effects of NSAIDs on the adapatational response to exercise in the elderly.
Figure 2: Two out of three studies find that NSAIDs blunt the satellite cell response to resistance training young people | A: Number of Pax7 cells expressed per number of myonuclei (in %) in muscle biopsies (vastus lateralis muscles) obtained before (pre) and 8 days after maximal eccentric exercise (no block and NSAID); B: Immunohistochemical staining with the use of Pax7 antibody to identify satellite cells on a muscle cross-section (7 m) taken 8 days after exercise (from Mikkelsen. 2009).
Bottom line: There's no reason to doubt the scientists' conclusion that "COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers" (Trappe. 2016). It is important however, that their results apply only to healthy elderly individuals.

Why only in the elderly? Well based on previous research, there's in fact good reason to doubt that similar benefits would have been observed in younger individuals. The hitherto published results in young people are mixed. A possible explanation for that would be the previously observed "impairment of satellite cell activity" (Schoenfeld. 2012) in response to chronic NSAID consumption - a side effect that may turn out to be detrimental in the long(er)-term, because unlike older individuals, in whom the satellite cell function is compromised, already (Thornell. 2011), young people's long-term gains appear to rely on the myostatin lowering recruitement of additional myonuclei.

Overall, the potential negative effects on satellite cell activity and thus long-term muscle growth, the lack of convincing evidence of benefits in younger individuals and, for young and old alike, the negative side effects of chronic NSAID use on your tendons, gut, kidney and other organs are three good reasons I certainly don't advise to seriously consider "supplementing" NSAIDs daily to augment your muscle gains | Comment on Facebook!
  • Mikkelsen, U. R., et al. "Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise." Journal of applied physiology 107.5 (2009): 1600-1611.
  • Schoenfeld, Brad J. "The Use of Nonsteroidal anti-inflammatory drugs for exercise-induced muscle damage." Sports medicine 42.12 (2012): 1017-1028.
  • Standley, R. A., et al. "Prostaglandin E 2 induces transcription of skeletal muscle mass regulators interleukin-6 and muscle RING finger-1 in humans." Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA) 88.5 (2013): 361-364.
  • Trappe, Todd A., and Sophia Z. Liu. "Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise." Journal of Applied Physiology 115.6 (2013a): 909-919.
  • Trappe, Todd A., et al. "Prostaglandin and myokine involvement in the cyclooxygenase-inhibiting drug enhancement of skeletal muscle adaptations to resistance exercise in older adults." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 304.3 (2013b): R198-R205.
  • Trappe, Todd A., et al. "COX Inhibitor Influence on Skeletal Muscle Fiber Size and Metabolic Adaptations to Resistance Exercise in Older Adults." J Gerontol A Biol Sci Med Sci (2016): Advance Access publication January 27, 2016.
  • Thornell, Lars-Eric. "Sarcopenic obesity: satellite cells in the aging muscle." Current Opinion in Clinical Nutrition & Metabolic Care 14.1 (2011): 22-27.