Can an NSAID a day keep muscle wasting away?

Sarcopenia (muscle loss with ageing) adversely affects mobility and stability and increases risk of falls – and mortality – after hip or femur fracture. Developing effective interventions has been a major goal for 30 years but so far only resistance exercise has shown any real benefit. However, this may change with the advent of drug treatments under development, like non-steroidal selective androgen receptor modulators (SARMS) and anti-myostatin antibodies. One promising but different approach has emerged from the increasingly strong evidence that sarcopenia is associated with, and may even be caused by, inflammation of muscle and the blood vessels supplying it. Older people with marked muscle wasting, tend to carry a high burden of pro-inflammatory markers (e.g. C-reactive peptide and cytokines, such as tumour necrosis factor alpha (TNF-α) and interleukins (including interleukin-6 (IL-6), IL-1a, IL-8 and IL-10); the plasma titre of these may even predict subsequent disability. There is, therefore, much interest in potential anti-inflammatory treatments of sarcopenia; the idea of being able to take a pill (especially a cheap one) to prevent muscle loss is tantalizing. Isabelle Rieu and colleagues, from the laboratory of Dominque Dardevet at the French National Institute for Agricultural Research (INRA) in Clermont-Ferrand, have produced important new evidence in a recent issue of The Journal of Physiology (Rieu et al. 2009) bolstering the argument that research on the possible effects of anti-inflammatories on the regulation of muscle mass is promising. In their elegant study, the French scientists supplemented the diet of old (20 months) rats for 5 months with 30 mg kg−1 day−1 of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen (IBU). In these rats (and in controls allowed to develop spontaneous low-grade inflammation as they aged) markers of inflammation in plasma, the rate of muscle protein synthesis (MPS) in vivo and muscle protein breakdown (MPB) in vitro were measured, together with the phosphorylation of kinases in the mTORc1 pathway (controlling translation from mRNA) and of the muscle transcription factor FOXO-3a (which regulates mRNA expression of ubiquitin ligases heading the ubiquitin–ATP-dependent proteolysis pathway (UPP)). After IBU treatment, 25-month-old rats showed less muscle wasting than untreated controls, which had more markers of inflammation in plasma. The apparent underlying mechanisms (see Fig. 1) involve modification of both MPS and MPB – not in the fasted state but rather after feeding, when normally MPS is raised by essential amino acids and MPB is inhibited by insulin. Whereas there were no demonstrable differences in either arm of protein turnover in the postabsorptive state, the non-treated rats showed the now well-recognized (Mosoni et al. 1995; Cuthbertson et al. 2005; Wilkes et al. 2009) phenomenon of anabolic blunting of both MPS and MPB on feeding, which was abolished in the IBU-treated animals. Maybe at last the simplistic idea of uncontrolled proteolysis eating up ageing muscle can be laid to rest. Figure 1 Potential mechanisms by which muscle protein maintenance may be influenced by the anti-inflammatory agents, ibuprofen and fish oil This study provides new evidence of one cause of the anabolic blunting of ageing as inflammation and demonstrates originally that it can be ameliorated by an NSAID. One fascinating piece of data is unexpected – the finding that FOXO-3a phosphorylation is increased in muscle of IBU-treated post-prandial rats compared to that of controls. This probably resulted in a nuclear-barring of phosphorylated FOXO-3a, providing a mechanistic explanation for the observed decreased MPB. Another surprising result, given that elsewhere (especially in human muscle), anabolic blunting is associated with decreased phosphorylation in the Akt/mTORc1 signalling family, was the lack of evidence of this in inflamed rats. Here again, it seems, we lack enough information on the control of muscle protein turnover to predict accurately the behaviour of the regulatory signalling system, as previously found in human muscle (Greenhaff et al. 2008). The mechanism of IBU action almost certainly involves decreasing throughput in the NFκB pathway via actions consequent to decreasing COX2 activity, with a subsequent decrease of PGE2-α (a lipid signalling molecule first shown to be catabolic by Robert Palmer and Peter Reeds at the Rowett Research Institute, 26 years ago; Reeds & Palmer, 1983). Whereas the details of the exact mechanisms (see Fig. 1) remain speculative, it is fascinating that the evidence (e.g. see Ryan et al. 2009) piling up in favour of an anabolic effect of fish oils (which also decrease muscle PGE2-α production) may involve similar distal mechanisms in ameliorating muscle wasting. How ironic it would be if big pharma, investing massively in SARMS and anti-myostatin antibodies were scooped by geriatricians prescribing nothing more expensive that daily NSAIDS (albeit judiciously, with a proton-pump inhibitor maybe? ) – and a kipper (or a bagel with extra lox) twice a week! Is that, and subsequent development, feasible? Just look at Dardevet's track-record of prefiguring discoveries in human muscle with careful studies in rats (Dardevet et al. 2000). He has form and it's a good bet that he will romp home again.