Identifying the mechanisms and biomarkers of anabolic steroid-induced muscle memory in mice and humans

Code: 23E04FP

It is well known that the use performance-enhancing substances by athletes provide an unfair advantage and doping is contrary to the ‘the spirit of sport’. However, a randomised response surveys conducted between 2011-2018 indicate that >15% of athletes have doped with banned substances. Yet in 2018, WADA reported only 2% positive samples, with hormone doping accounting for >50% of adverse analytical findings. These statistics suggests that micro-dosing, off-competition doping and cyclical (on/off)/pyramiding patterns of administering anabolic steroids (AAS) have allowed athletes to evade current detection methods, while beneficial for building muscle mass, strength and performance. In addition, drug administration studies in humans have demonstrated that testosterone dose-dependently increases satellite cell and myonuclei number, muscle fibre cross sectional area (CSA) and induces hypertrophy of muscle fibres. These benefits may remain long after cessation of AAS use and/or detraining leading a muscle atrophy, when a new stimulus (i.e., returning to training) is given, the performance is enhanced, a phenomenon known as “muscle memory”. The “muscle memory” associated with AAS could explain why androgen cycling has been so effective for doping athletes. AAS treatment in mice for 14 days has been shown to increase myonuclei number by 66%, and these are retained despite drug withdrawal and contribute to faster muscle growth in response to muscle overload (Egner et al, 2013). These findings indicate that even brief exposure to AAS may provide long-term benefits for muscle performance. Increasing understanding of the mechanisms associated with AAS muscle memory is thus vital for enhancing anti-doping detection. Other mechanisms, besides myonuclei accretion/retention, have also been implicated with the muscle memory phenomenon, and the understanding of this process is crucial for the identification of long-term biomarkers. Therefore, the aim of this research is to identify relevant biomarkers associated with past-AAS use. Building on previous work, we will generate and characterise a mouse model of AAS muscle memory and explore the associated mechanisms using transcriptomic, phosphoproteomic and metabolomic approaches. In our previous research funded by a WADA research grant (16E11FP), we have established a tissue biobank (muscle biopsies, saliva, urine, serum) from powerlifters that either do not use AAS, actively use AAS or have previously used AAS. Guided by findings in mice, we will examine the utility of these markers for identifying current and past-AAS use in our biobank of tissues. Our findings are envisaged to enhance anti-doping detection, provide guidance for appropriate punitive measures in response to positive tests, and contribute to ongoing debates regarding transgender athlete inclusion in elite competition.