Mechanism of eccentric training augmentation of muscle adaptation in humans and the potential negative impact of non-steroidal anti-inflammatory drugs

This project is aimed at elucidating how long-term physical training involving both lengthening and shortening muscle contractions increases muscle size and strength in humans above shortening contractions alone, and whether chronic ingestion of non-steroidal anti-inflammatory drugs impairs this process. In collaboration with UK Sport, the BBSRC has made funding available for research applications that will specifically utilise 'fundamental bioscience to provide new insights into the stress and adaptation required to maximise physical potential', and by doing so will 'address many of the major challenges facing high performance sport in the UK through athletic training and performance.' This project meets this remit on two fronts: (i) Although we know that resistance training which involves a combination of lengthening and shortening muscle contractions results in greater muscle mass and strength gains than training involving only shortening contractions, and is used widely by athletes to maximise performance gains, our understanding of the mechanisms by which this is achieved is at a rudimentary level. Furthermore, we know nothing about the time-course of muscle performance gains and physiological changes that occur during this type of training. It is known that muscle inflammation is greater after a single bout of lengthening contractions compared to shortening contractions, which may be important. Therefore we aim to use a basic bioscience approach to examine whether augmented muscle growth factor expression and muscle specific stem cell proliferation, that we believe occur secondary to exercise induced muscle inflammation, is the mechanism by which a sustained period of training involving combined lengthening and shortening contractions augments muscle mass and strength gains over training involving only shortening contractions. This aspect of the project will provide detailed, broad-based mechanistic insight of how resistance exercise training results in positive muscle adaptation and functional gains in humans. In addition to being of importance to our fundamental understanding of physiological adaptation to exercise stress, and thereby maximising athletic performance, it has wider relevance to our understanding of how we might minimise the loss of muscle mass that accompanies ageing (sarcopaenia). (ii) Non-steroidal anti-inflammatory drugs (NSAID's) are widely used in top level sport as a prophylactic agent to seemingly minimise pain and injury and maximise training adaptation, but given the emerging role of inflammation in stimulating muscle growth responses (including muscle stem cell activation), there is a distinct possibility that chronic prophylactic use of NSAID's may impair muscle adaptation to resistance training, thereby blunting athlete performance development (in addition to being unsafe). The present project will address a major challenge facing high performance sport in the UK by determining whether NSAID ingestion during a programme of resistance training can blunt training induced increases in muscle function (by attenuating muscle inflammation, muscle growth factor responses and stem cell activation and proliferation). Clearly therefore this project will provide valuable, novel information concerning the potential negative effect of prophylactic NSAID use by athletes, thereby fulfilling the requirement of UK Sport of linking fundamental biological research to high performance sport.

Using volunteers accustomed to resistance training, this project will test the hypothesis that augmented muscle adaptation seen over 84 days of combined eccentric and concentric resistance training (reflected by greater muscle mass, muscle fibre area and strength changes when compared to workload balanced concentric training performed by the contra-lateral limb in the same individuals) is preceded by greater exercise induced changes in inflammatory gene expression, 'patches' of denatured myofibrillar proteins, greater suppression of myostatin mRNA and protein expression levels, augmented MyoD mRNA and protein expression, and greater satellite cell activation and proliferation. Non-steroidal anti-inflammatory drugs (NSAID's) are used prophylactically in top level sport to maximise training adaptation, but given the emerging role of inflammation in stimulating muscle growth responses, there is a distinct possibility that chronic prophylactic use of NSAID's may impair muscle adaptation to resistance training, thereby blunting athlete performance development (in addition to being unsafe). This project will therefore also test the hypothesis that NSAID ingestion during chronic concentric training and combined eccentric and concentric training in volunteers accustomed to resistance trained will blunt training induced increases in muscle mass, fibre area and strength gains by attenuating muscle inflammation, and as a consequence blunt MyoD mRNA and protein increases, myostatin mRNA and protein suppression, and satellite cell activation and proliferation. We predict that the biggest inhibitory effect of NSAID's will be seen with combined eccentric and concentric training, where the greatest inflammatory responses will occur.

What will be done to ensure that potential beneficiaries have the opportunity to engage with this research? The stated aim of the call in High Performance Sport as a Model for Biological Research is to utilise 'fundamental bioscience to provide new insights into the stress and adaptation required to maximise physical potential', and by doing so can help 'address many of the major challenges facing high performance sport in the UK through athletic training and performance.' It is clear therefore that one of the primary beneficiaries of this work should be athletes. Athletes are now being educated on maximising training adaptation and the use of NSAIDs. However, having a more fundamental understanding of the impact of eccentric exercise and NSAID use on physiological adaptation in human muscle will be a very valuable addition to this education. It has been agreed by the PI and Dr Scott Drawer (Head of Research and Innovation, UK Sport) that progress and outcomes of the research will be disseminated using the following specific milestone events: (i) Communication via the UK Sport web site (http://www.uksport.gov.uk/), press releases and the wkly UK Sport newsletter at the onset (May 2011) and end of the project (April 2013). (ii) Direct engagement with end users by the applicants, the Post-doctoral Fellow and UK Sport using the following vehicles: UK Sport annual 'performance conference' English Institute for sport annual 'conference' Technical forums - coaching and institute staff (iii) Basic scientific meetings, attended by the applicants, the Post-doctoral Fellow and UK Sport, in particular a high profile international meeting being jointly hosted by the Physiological Society and British Pharmacological Society to showcase British sport and exercise science and medicine entitled 'The 2012 Games: the Biomedical Basis of Elite Performance', Queen Elizabeth Conference Centre London, March 2012 (PI Chair of the Conference Organising Committee). It is also clear that the members of the general public who exercise on a regular basis, or elderly individuals attempting the maintain muscle mass into old age by using resistance exercise training, could benefit from the current research. Dissemination of the project and its findings to the general public will therefore be important. This will be achieved by the following milestone events: (i) Press releases via the Public Relations Office of the University of Nottingham (ii) Local and national radio interviews (iii) Press releases associated with basic science meetings, not least the 2012 showcase London meeting (see above). Collaboration and Co-production One positive aspect of generating this application is good interaction has developed between UK Sport and the PI. As a result, plans are being formulated for UK Sport to access the knowledge base and facilities of the University of Nottingham to assist them in their understand of the use of eccentric training to stimulate adaptation, particularly in an applied setting. Exploitation and Application It is apparent that the research outcomes could be of sufficient impact to translate effectively to further research. In particular, the evolution of eccentric training programmes in an applied athletic setting, building upon a strong interaction developing between UK Sport and the PI (see above). Away from sport, the potential positive effect of eccentric training in stimulating muscle mass and function benefits in people experiencing muscle wasting is important, particularly in the healthy ageing population. Furthermore, it would be pertinent to address the potential negative impact of NSAID ingestion in this population, particularly given the widespread use of NSAID's amongst elderly people. This area of research is of significant importance to most research funding bodies, including being a priority area for the BBSRC.