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

Lead Research Organisation: University of Nottingham
Department Name: School of Life Sciences

Abstract

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.

Technical Summary

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.

Planned Impact

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.

Publications

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Atherton PJ (2016) Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence. in American journal of physiology. Endocrinology and metabolism

 
Description Acute non-steroidal anti-inflammatory drugs (NSAIDs, such as Ibuprofen) blunt exercise mediated increases muscle protein synthesis in young volunteers, which may have consequences on long term gains in muscle mass. Surprisingly, chronic NSAID ingestion results in greater muscle gains during resistance exercise training in older volunteers. We therefore determined the impact of chronic NSAID administration on muscle cross-sectional area (CSA), volume and the cellular and molecular regulators thought to control muscle mass gains during 12 weeks of resistance exercise training in healthy male volunteers, and the time-course of any effect observed. We have been able to show that chronic NSAID administration increased muscle CSA and volume gains in these young volunteers and that this occurred predominantly between 4 and 12 weeks of training. This anabolic effect appears to be due at least in part to NSAID modulation of muscle TNFa and MyoD protein expression.
Exploitation Route We are currently undertaking some additional analyses on samples from the study, but then plan to apply our findings to older volunteers and/or patients with chronic inflammatory conditions in muscle to determine whether exercise plus NSAID administration can benefit mass and functional gains. This will require further funding to be secured.
Sectors Healthcare

 
Description Our findings demonstrate that blunting exercise induced muscle muscle inflammation using a non-steroidal anti-inflammatory drug intervention can lower muscle inflammation and stimulate muscle mass gains. This therefore has direct applicability to ageing and age related inflammatory diseases where muscle metabolic dysregulation has been shown to prevail and can possibly be ameliorated by such drug intervention.
First Year Of Impact 2014
Sector Healthcare
Impact Types Societal,Economic

 
Description ARUK: policy statement on physical activity and musculoskeletal decline
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Arthritis Research UK Centre for Sport, Exercise and OA.
Amount £2,999,582 (GBP)
Organisation Versus Arthritis 
Start 09/2013 
End 08/2018
 
Description The impact of high load eccentric exercise on muscle functional loss and recovery and muscle protein synthetic rates and in healthy, young male volunteers unaccustomed to exercise training.
Amount £145,965 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 06/2014 
End 06/2015
 
Description ARUK Centre for Sport Exercise and Osteoarthritis 
Organisation Nottingham University Hospitals NHS Trust
Department Nottingham University Hospitals Charity
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We are undertaking a project investigating the molecular regulation of muscle insulin resistance and mass loss as a result of ankle fracture and subsequent surgery. We are also investigating the impact of early mobilisation of the joint on the restoration of muscle mass, insulin sensitivity and function during rehabilitation following surgery.
Collaborator Contribution All patient and surgical contributions to the project
Impact This project involves clinicians, physiotherapists and scientists. WE have just gained ethical approval for this project.
Start Year 2014
 
Description ARUK/MRC Centre for Musculoskeletal Ageing Research 
Organisation University of Birmingham
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint bid from Universities of Birmingham and Nottingham
Start Year 2012
 
Description Glaxosmithkline (eccentric muscle damage) 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Design and execution of a study aimed at investigating the impact of high load eccentric exercise on muscle functional loss and recovery and muscle protein synthetic rates and in healthy, young male volunteers unaccustomed to exercise training
Collaborator Contribution Funding the volunteer study in Nottingham and undertaking muscle biopsy and blood analyses
Impact No outputs yet as collaboration still ongoing.
Start Year 2013
 
Title Muscle eccentric damage model (with GSK) 
Description This is a model developed for use in human volunteers to assess the impact of drug interventions on facilitating muscle metabolic and functional recovery following acute trauma. Funding from GSK. 
Type Support Tool - For Fundamental Research
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2014
Development Status Under active development/distribution
Impact See above 
 
Description ARUK advisory panel meeting on physical activity 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interaction with ARUK about their policy document relating to exercise and musculoskeletal health in the context of OA.

Stimulated significant interest with ARUK
Year(s) Of Engagement Activity 2014
 
Description Attendance Integrative Physiology of Exercise Meeting in USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Poster presentation on gene expression changes from this project
Year(s) Of Engagement Activity 2018
 
Description European College of Sports Science Symposium - control of skeletal muscle mass with ageing: effects of exercise, inactivity and inflammation. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talk sparked discussion and interaction

Post talk discussion (students asking for papers and interaction)
Year(s) Of Engagement Activity 2014
 
Description Keynote lecture, American College of Sports Medicine Annual Meeting 2018, Minneapolis, USA 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Keynote lecture, American College of Sports Medicine Annual Meeting 2018, Minneapolis, USA
Year(s) Of Engagement Activity 2018
 
Description Physiological Society Conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact A symposium on inactivity and musculoskeletal degeneration in Ageing at a Physiological Society meeting in Edinburgh in 2014
Year(s) Of Engagement Activity 2014
 
Description Plenary lecture British Society for Research into Ageing (attended by scientists and funders) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact It stimulated thought about the role of inactivity in driving ageing processes (or even whether we are confusing inactivity processes with ageing processes)

Lots of discussion in months post event on controversial topic.
Year(s) Of Engagement Activity 2014
 
Description Strength capacity and training in elderly and statins and physical training 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Symposium on "Aging and physical training" Centre for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen. Three day PhD course of workshops and lectures.

After my talk a grant application was generated (EU Horizon 2020) and a PhD studentship applied for a training fellowship to work in my laboratory
Year(s) Of Engagement Activity 2013
 
Description Universities of Ghent and Leuven Inter-university Doctoral Training School 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Talking sparked discussion amongst PhD students attending the doctoral training course

Change way of thinking about inflammation amongst young scientists
Year(s) Of Engagement Activity 2014