ANTI-MYOSTATIN DRUGS: THE NEW ANABOLIC STEROIDS?

1.   Myostatin function

  Myostatin is a key regulator of muscle mass: it is a peptide that potently inhibits muscle growth. Experimental myostatin knockout in mice or some natural mutations of the myostatin gene increase muscle mass dramatically in mice, cattle and human beings. The case of a boy with twice the normal muscle mass due to a "natural" myostatin mutation was reported widely.

2.   Anti-myostatin drugs

  Muscle wasting is a problem in a wide variety of conditions that include normal ageing, HIV/AIDS and some forms of cancer. Anti-myostatin therapy seems suitable for many of these conditions. Myostatin is an "easy" drug target because it can be targeted extracellularly, acts tissue specific and because endogenous inhibitors can be mimicked. It is also a commercially attractive drug target because it is suitable for the prevention of muscle wasting in the whole elderly population. This could be a crucial intervention leading to greater independence in ageing Western societies.

3.   Current drug development

  Wyeth are currently testing the effectiveness of a monoclonal anti-myostatin antibody (MYO-029) on patients with facioscapulohumeral muscular dystrophy (FSHD), Becker muscular dystrophy (BMD) and limb-girdle muscular dystrophy (LGMD). Results are expected for late 2006. Thus it seems likely that anti-myostatin drugs will become available well before the 2012 London Olympics. Bogus anti-myostatin treatments (Myozap) are commercially available showing the desire of bodybuilders and others to achieve muscle growth by inhibiting myostatin.

4.   Likelihood of abuse and dangers

  Many doping scandals are linked to bodybuilders or strength/power athletes taking agents that aim to increase muscle mass. Thus muscle growth-promoting myostatin inhibitors are likely to be (ab-) used once they become available. At the same time myostatin inhibitors are probably safer than anabolic steroids because myostatin action is muscle specific whereas anabolic steroid affect many organs other than muscle. Anti-myostatin drugs are likely to be the new anabolic steroids.

5.   Challenges for drug testers

  Monoclonal antibodies (ie the anti-myostatin treatment currently tested) is a new kind of doping agent. It should be easy to detect these antibodies in blood because they are raised in another species. However we are unsure whether such antibodies or their degradation products can be detected in urine. It is, however, likely that future myostatin treatments will not be limited to monoclonal antibodies. There is a series of papers reporting the existence of endogenously produced myostatin-inhibiting peptides. These are nature's models for anti-myostatin therapy and it seems likely that pharmaceutical companies or others will attempt to copy these. Myostatin-inhibiting compounds might be detected by screening libraries of chemical compounds.

6.   Executive summary

  Myostatin inhibitors are likely to become available well before the 2012 Olympic Games in London. There is little doubt that they will be abused by bodybuilders and other strength/power athletes. Myostatin inhibitors are likely to be safer than anabolic steroids, growth hormone and clenbuterol which are drugs currently used to attempt to increase muscle mass. If monoclonal anti-myostatin antibodies are used to inhibit myostatin then the detection in blood should be easy but it is unclear whether the detection in urine is feasible. Research is needed to develop urine-based detection methods.

ADDITIONAL INFORMATION

The potential for different HETs, including drugs, genetic modification and technological devices, to be used legally or otherwise for enhancing sporting performance, now and in the future

  I wish to comment on the likelihood that new HETs will be developed and used in sport. Currently molecular biologists and sports and exercise scientists discover at new mechanisms and genetic variations that regulate factors such as muscle growth, capillarity, oxygen transport capacity, energy metabolism and heart growth. Mechanistic knowledge allows us to understand how physical training induces adaptations. It is also crucial knowledge for developing treatments (or HETs) that target these mechanisms for therapeutic aims. For example, the discovery of erythropoietin (EPO) laid the foundation for the synthesis of this hormone. Synthetic EPO can be used to increase red blood cell production in patients with low red blood cell count and in endurance athletes where it increases oxygen transport capacity. The discovery of the muscle growth inhibitor myostatin triggered the development of monoclonal antibodies against myostatin. These can potentially be used to increase muscle mass in > 75 year olds or in strength athletes. Novel HETs are likely to be developed especially for mechanisms that can be targeted extracellularly (both EPO and myostatin can be targeted extracellularly). In my opinion serious genetic manipulation of athletes is unlikely to be attempted before 2012 because it is technically difficult and the type of desired and side effects are unclear. To conclude it seems likely that novel HETs will be developed and used by athletes before the London 2012 Olympics.

Steps that could be taken to minimise the use of illegal HETs at the 2012 Olympics

  I don't have any new ideas to contribute.

The case, both scientific and ethical, for allowing the use of different HETs in sport and the role of the public, Government and Parliament in influencing the regulatory framework for the use of HETs in sport

  Without being a legal expert I feel that there is a case for a strong legal deterrent against using the most dangerous doping agents such as EPO. Seven elite cyclists died of sudden cardiac death between 2003 and 2004 alone (The Observer, Sunday 7 March 2004) and it seems very likely if not obvious that most if not all of these deaths are related to the use of EPO or related agents. Thus, government may wish to consider strengthening the law to try to prevent the use of such agents by athletes.

  For all other agents I feel that the anti-doping policies by most sporting associations are adequate. The government and parliament should consider lobbying for removing sports from the Olympic programme that do not sufficiently control doping.

The state of the UK research and skills base underpinning the development of new HETs, and technologies to facilitate their detection

  Sports and exercise research is probably less well funded in the UK than in the US or Scandinavia. There are several researchers [Goldspink, Harridge, Montgomery (London), Wagenmakers (Birmingham), Rennie, Greenhaff (Derby/Nottingham). Harris (Chichester), Maughan (Loughborough) and Baar, Sakamoto, Hardie (Dundee)] that make important contributions to the discovery of exercise mechanisms and genetic variations that are related to performance, therapies and HET development. Additional financial support for such research is desirable.

  It is unfortunate that the practical skills (ie biochemical, molecular biology and genetic techniques) necessary for mechanistic exercise research are not often taught as part of sports and exercise science degrees. At Aberdeen we have thus decided to develop a MSc in Molecular Exercise Physiology where hands on training in such techniques is a key component. It is desirable that such skills are also developed as part of other sports and exercise science programmes.

  The great challenge for HET detection is the detection of HETs or their degradation products in urine unless blood samples are taken. Some new classes of HETs (for example antibodies) require novel approaches for their detection in urine which may be difficult.

May 2006