01 July 2013

IL-1Ra as a performance enhancing drug? New doping for ultramarathon and endurance activities

This weekend the 100th edition of Tour de France started in Porto-Vecchio, Corsica. I have followed the race for many years each summer and I was completely thrilled by the repeated victories of Lance Armstrong.  Needless to say, the revelation that he all these years deviously had used prohibited substances to enhance his performance was a huge disappointment and I regard it as a very dark moment for not only this race but for all endurance sport competitions – if he could get away with this for so many years how many else have done so and are continuing to do so? I am a positive person and strongly believe that most athletes are honest and I think for instance runners like Kilian Jornet and Emelie Forsberg, who by the way placed first and second in the Mont Blanc Marathon this weekend, certainly do not use prohibited substances to enhance their performance. Kilian is clearly a physical phenomenon and his training is clearly in line with his performances as described for instance in articles in New York Times and Runners World.

Looking at the advancements in performance enhancing drugs I think we are moving  away from traditional blood doping through auto-transfusions with the athlete’s own blood or by stimulating production of the oxygen-bearing red blood cells through erythropoietin (EPO). To speculate, I think the future probably lies more on the cellular level with a focus on regeneration of tissues and repairing damages induced by muscular stress. A key component in regeneration is the immune system as it has become clear during the past few years that it is not only involved in protecting us against outside threats like bacteria, viruses and parasites, but also becomes activated by damage induced by for instance strenuous physical activity. The immune system is heavily involved in delayed onset muscle soreness (DOMS)/muscle fever – the question is how it is involved in the development and resolution of DOMS (see for instance review articles by Gleeson M. J Appl Physiol 2007; 103: 693–699; Walsh NP et al. Exerc Immunol Rev. 2011; 17: 6-63 and Paulsen G, et al. Exerc Immunol Rev. 2012; 18: 42-97). Interestingly, the role of muscles has been revised by new research showing that they act as a secretory organ important for the general health and well-being and playing an important part in the immune regulation of the body through anti-inflammatory effects (Pedersen BK & Febbraio MA. Nat Rev Endocrinol. 2012; 8: 457-65 and Petersen AM & Pedersen BK. J Appl Physiol 2005; 98: 1154-1162).

Key mediator of the immune system in response to stress and injuries through the so called inflammasome is the signal-molecule cytokine interleukin-1 and its receptor (reviewed in for instance Rathinam VA et al.  Nat Immunol. 2012; 13: 333-2 and Dinarello CA et al. Nat Rev Drug Discov. 2012; 11: 633-52). I will here not go into the details of IL-1 and its importance for a multitude of clinical disorders, but briefly highlight some of the evidence for the emerging role for this cytokine in exercise induced damage. One of the effects of IL-1 is to induce fever through its role as a pyrogen and already in 1983 it was shown that exercise could let to production of an endogenous pyrogen later shown to be IL-1 (Cannon & Kluger  Science. 1983; 220: 617-9; Cannon et al Am J Physiol. 1989 257:R451-5).

Following systemic release of IL-1 in the body after strenuous exercise there is also a concomitant increase in the receptor IL-1Ra, which act as an endogenous self-control of the IL-1 response and limits inflammation – it is known that genetic deficiency of IL-1ra is the cause of several severe fever disorders so this is an adequate and physiological response. Interestingly, it has been shown that variation in the gene for IL-1Ra (VNTR IL-1RN polymorphism) is associated with athlete status (Cauci et al. BMC Med Genet. 2010; 11: 299). In a large Italian study of Italian they found a dose-effect relationship with the 1/2 IL-1RN genotype being 2-fold more frequent in professional than in recreational athletes and 3-fold more frequent in professional athletes than in non-athletes. How this is occurring is unclear, but one hypothesis would be that the 1/2IL-1RN genotype could favor muscle repair in athletes through higher circulating or local levels of IL-1Ra.

However, a recent study indicate that the circulating levels of IL-1Ra is actually not higher in endurance trained athletes compared with recreationally active men, but this small study only evaluated the effect after a short moderate exercise so more studies are clearly needed (Scott JP et al. Eur J Appl Physiol. 2013; 113: 1871-82). The hypothesis that IL-1Ra is involved in muscle repair after exercise would implicate that recombinant IL-1Ra might be beneficial after strenuous exercise in the recovery process and in healing of for instance DOMS. Recombinant IL-1Ra is available as the drug Anakinra (Kineret®) and this might thus be an interesting compound to test whether it would be performance-enhancing or not, as it might well be during a prolonged competition such as Tour de France where rapid recovery between stages is paramount. One major risk with this would of course be the immune suppressant effects of the drug, but as it is widely used and already indicated for rheumatoid arthritis it can certainly be tested in clinical trials. Looking at a website for clinical trials, www.clinicaltrials.gov,  I can see that there currently is one trial evaluating Anakinra in exercise ongoing done by a group led by Prof Donath in Zürich, but this trial is focusing only on the effects after a one-hour bout of exercise not likely to induce moderate or severe muscle damage (NCT01771445). In line with the hypothesis that IL-1Ra might be beneficial for DOMS is reports that indicate that new exercise, generating more IL-1Ra, is beneficial through the so called Repeated Bout Effect (RBE) (reviewed in for instance Assumpção Cde ScientificWorldJournal. 2013; 2013: 189149). The role of IL-1Ra and related substances in the immune system following exercise is really fascinating and I think we will learn and hear a lot more about this in the coming few years.

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