Non‐steroidal anti‐inflammatory drugs may blunt more than pain

In this issue of Acta Physiologica, Lilja et al1 provide novel insights into the effects of consuming high doses of non-steroidal anti-inflammatory drugs (NSAIDs) on exercise-induced muscular adaptations. NSAIDs are routinely administered to relieve symptoms associated with delayed onset muscle soreness (DOMS) and restore normal physical function following intense physical activity. Millions worldwide report the daily intake of NSAIDS, and their usage is especially common in athletes and those who partake in rigorous exercise.2 The analgesic effects of NSAIDs are purported to be related to an inhibition of the cyclooxygenase (COX) family of enzymes involved in the conversion of arachidonic acid to pro-inflammatory prostanoids. Three COX isoforms have been identified: COX-1, COX-2 and COX-3. However, only the COX-1 and COX-2 isoforms are thought to be expressed in skeletal muscle and play a role in the post-exercise response. Following their synthesis, prostanoids are liberated from the cell and interact with cell surface receptors where they exert their biological actions in an autocrine/paracrine manner. Theoretically, reducing prostanoid-induced inflammation via NSAID administration leads to an alleviation of post-exercise pain and oedema, although it remains equivocal whether blocking these enzymes actually promote a therapeutic effect in practice.3 Emerging evidence indicates that prostanoids are also involved in the remodelling of muscle tissue pursuant to exercise, conceivably by mediating upstream signalling of anabolic regulators such as PI3K and extracellular signal-regulated kinases.4 Moreover, there appears to be a direct effect of prostanoids on satellite cell-derived myonuclear accretion, which in turn mediates increases in skeletal muscle hypertrophy.5 Although these data indicate an important role for COX in exercise-induced muscle development, research is contradictory as to whether blunting its activation impairs exercise-induced muscle growth. Studies of the effects of NSAIDs on the acute muscle protein synthetic (MPS) response following resistance training have generally shown mixed results, with a majority of studies failing to demonstrate detrimental effects of these drugs on anabolism.6 Alternatively, the preponderance of evidence indicates that NSAIDs blunt satellite cell activity.6 Given that changes in muscle cross-sectional area correspond with an increase in myonuclei (ie, myonuclear domain theory), satellite cells are proposed to be critical to exercise-induced hypertrophic adaptations as they donate nuclei to the myofibre to support continued muscular development. It could therefore be inferred that NSAID administration, while perhaps not impacting acute measures of MPS, would be deleterious to long-term muscle growth by interfering with the ability for muscle tissue to expand its synthesis of proteins needed for repair and remodelling over time. Interestingly, previous longitudinal research has not shown that NSAIDs impair muscle hypertrophy in young individuals when taken during the course of a regimented resistance training programme and, in fact, there is evidence that the drugs confer a positive hypertrophic effect in elderly subjects.6 With respect to the elderly, the disconnect between logical inference and practical application may be explained by the fact NSAIDs counteract the chronic inflammation that is prevalent in this population. Importantly, chronic inflammation is known to interfere with anabolic processes. Thus, any negative impact of NSAIDs on muscle development is conceivably cancelled out by the favourable anti-inflammatory effects. The only previous study carried out in young subjects found no significant differences between consuming 400 mg of ibuprofen only on training days versus a placebo following 6 weeks of regimented resistance exercise.7 The low NSAID dose (800–1200 mg/week) and short study duration in this trial limit the generalizability of findings. The study by Lilja et al1 in this issue of Acta Physiologica fills an important gap in the literature, helping to further our understanding of how chronic NSAID administration affects young, healthy individuals engaging in regular resistance training. Compared to previous work by Krentz et al (63), the study used a higher dosage (1200 mg/day of ibuprofen) more commonly consumed in an athletic population, as well as employing a longer study period (8 weeks) that allowed for better assessment of changes in muscular outcomes. The authors found that high-dose intake of ibuprofen throughout the study period significantly attenuated gains in quadriceps muscle mass compared to a low-dose provision of aspirin. In an attempt to determine potential mechanistic explanations for their findings, the researchers examined various molecular responses. Of those studied, only IL-6 showed a significant interaction, with a downregulation of this pro-inflammatory cytokine seen in the ibuprofen condition versus an upregulation in those taking aspirin. There is some evidence that the acute post-exercise production of IL-6 may promote anabolic effects; however, it remains to be determined whether its suppression via NSAID consumption is responsible for an impairment of muscle development. Regardless, the findings clearly indicate that the COX pathway and its associated synthesis of prostaglandins play an important role in the hypertrophic response to resistance training. Moreover, the study provides compelling evidence that athletes concerned with maximizing muscular adaptations should limit consumption of ibuprofen, keeping both the dose and frequency of usage low. The novel findings in the study by Lilja et al1 will hopefully provide an impetus for additional research on the COX pathway and its mechanistic role in exercise-induced hypertrophy. This could shed important insights on the processes of regulating muscle development, as well as facilitating the creation of possible therapies for conditions such as sarcopenia and cachexia. In addition, ibuprofen is a non-selective COX inhibitor that acts on all isoforms of the enzyme family. There is evidence that COX-1 may be involved in the anabolic response to exercise while COX-2 may be more specific to muscle injury. Future research should therefore endeavour to explore whether a selective COX inhibitor may provide desirable benefits to an athletic population without the noted downside. The author reports no conflicts of interest with this paper.