Sarcopenia (Part 2)

The inaugural UK conference on sarcopenia was held in central London on 9th July 2013.

Sarcopenia

Sarcopenia

Delegates included clinicians, therapists, nutritionists and scientists, with representatives from Spain, Belgium, the Netherlands, Poland, the Ukraine, the United States and Japan.

Mitochondrial dysfunction

Professor Doug Turnbull, Professor of Neurology at Newcastle University and Director of the LLHW Centre for Ageing and Vitality and of the Wellcome Trust Centre for Mitochondrial Research, outlined the role of mitochondrial dysfunction in the development of sarcopenia. He explained that two types of mitochondria are found in muscle, subsarcolemma and intermyofibrillar: the latter are the majority and are heavily networked. Numerous studies have shown a decline in mitochondrial oxidative metabolism with age, and specifically that segments of muscle have severe deficiency. The mechanism for this involves high levels of mutations within the mitochondrial genome, with evidence that this leads to muscle fibre splitting and breakage. There is also increasing evidence that mitochondria are implicated in motor neurone loss, typically reduced by 34 per cent in people aged 80-90 years compared to those aged 30-40 years. Professor Turnbull concluded by commenting that exercise has been demonstrated to increase mitochondrial density and function, highlighting a possible mechanism for the treatment of sarcopenia.

The final speaker in the morning was Professor Paul Greenhaff, Professor of Muscle Metabolism at the University of Nottingham and Deputy Director of the MRC/Arthritis Research UK Centre for Musculoskeletal Ageing Research. Professor Greenhaff explained the importance of both quantity and quality of muscle in older people, with a reduction in muscle protein synthesis in response to protein nutrition with age, accompanied by increased myocellular lipid accumulation. He highlighted the likely equal importance to the aetiology of sarcopenia of ageing of episodic acute inactivity, infection and inflammation. Bed rest causes a loss of muscle mass, which is exacerbated by trauma or illness, such as hospitalisation. Immobilisation leads to a reduction in muscle protein synthesis, and infection and inflammation further exacerbate this reduction and also lead to increased protein degradation.

Lunch allowed time to review posters ranging from development of potential biomarkers of sarcopenia through epidemiological prevalence studies to translation of possible screening tools into clinical settings.

Sarcopenia case finding

The afternoon had a focus on clinical interventions for sarcopenia. Finbarr Martin, Professor of Medical Gerontology at King’s College London, discussed the move towards a consensus definition of sarcopenia in clinical practice and research. Although sarcopenia has been defined as the loss of skeletal muscle mass and strength with age, an operational definition lacks worldwide consensus. Professor Martin outlined the need for a clear definition for clinical practice (to increase awareness, drive treatment efforts and monitor effects of therapies) and for research (to focus attention on underlying mechanisms and enable standardised comparisons between epidemiological and intervention studies). He described how the European Working Group on Sarcopenia in Older People, of which he was a member, has developed an algorithm for sarcopenia case-finding in older people based on measurements of gait speed, grip strength and muscle mass (Age and Ageing 2010; 39(4):412). Further work is required to validate these measures in defined clinical groups.

Dr Carolyn Greig, Senior Lecturer in Nutrition and Ageing at the University of Birmingham, is a translational scientist and physiologist. She discussed the functional importance for older people of maintaining sufficient muscle mass and strength to keep above the ‘threshold for independence’. Current NHS physical activity guidelines are designed for health rather than avoidance of sarcopenia, and include 150 minutes/week of moderate intensity exercise to include resistance exercise. Dr Greig explained that the response of older people to exercise, in terms of muscle protein synthesis, is blunted compared to younger people. The addition of protein supplements may have a modest impact. Recent research has focussed on reducing sedentary behaviour. Accelerometry data has identified that up to 60 per cent older people’s waking time may be sedentary, and there is current research interest in strategies such as fragmentation of sedentary time by intermittent low volume activity.

Sian Robinson, Professor of Nutritional Epidemiology at the MRC Lifecourse Epidemiology Unit, University of Southampton, spoke about dietary interventions for sarcopenia. Professor Robinson explained that existing observational studies have demonstrated the potential importance of adequate intake of energy, protein and micronutrients. Some studies have demonstrated an improvement in muscle mass with nutrient supplementation combined with exercise, but these effects are inconsistent and the underlying mechanisms are poorly understood. It is possible that interventions with whole diets, such as the Mediterranean diet, hold more promise, but further research is required.

Cannot, will not or should not

The final speaker was Professor Marion McMurdo, Head of Ageing and Health at the University of Dundee, and lead for the NIHR Age and Ageing Speciality Group. Her talk was a tour de force with regard to drug treatment for sarcopenia. Professor McMurdo commented that as geriatricians, we have a problem in implementing exercise based interventions, since evidence suggests that one third of older people ‘cannot, will not or should not’ engage in exercise. Thus there is a need for a pharmacological treatment for sarcopenia.

Several treatments have been tried over the years and range from peroxisome proliferator activator receptor (PPAR) delta agonists in animal models, exogenous Growth Hormone (GH) and testosterone in humans. These trials have met with mixed success. In the case of GH and testosterone, although muscle mass increased with supplementation, there was less effect on function and adverse effects are likely to prohibit their widespread use in sarcopenia. There are currently phase two trials of Selective Androgen Receptor Modulators (SARMs) in patients with cachexia associated with malignancy – these drugs selectively bind the androgen receptor in muscle and bone rather than prostate and confer the beneficial effects of testosterone on these tissues. In a small 16 week double blind placebo controlled trial of patients with advanced malignancy, the use of a SARM was associated with higher lean mass compared to the control group. This class of drugs may be important in future trials involving patients with sarcopenia where mass as well as strength and function are endpoints.

Much attention has been given to myostatin after the observation that naturally occurring mutations leading to a lack of myostatin in certain breeds of cattle and dogs were associated with increased musculature. However, despite the fact that animals without myostatin have increased musculature, their muscle function e.g. running speed has been shown to be poor; more muscle mass does not necessarily translate into better physical performance. Finally, I/I polymorphism of the ACE gene leading to a lower level of angiotensin converting enzyme is associated with an increase in type I myofibres and better muscle endurance. This led to the hypothesis that ACEi use may confer similar benefits on endurance. Evidence so far has shown that ACEi use improves exercise capacity measured by the 6 metre walk test in older heart failure patients and has been shown to slow the rate of decline in walking speed. In a study conducted in Dundee, a 20 week trial of an ACEi was associated with an increase in walking distance. However the same group performed a trial of ACEi with exercise vs ACEi alone for 20 weeks and found no difference in physical performance. Nevertheless there may still be potential in pursuing ACEis as a potential therapeutic option for sarcopenia – old drug, new tricks.

The conference ended with closing remarks from Professor Aihie Sayer. She described sarcopenia as a major new clinical area, with a successful track record of innovative research in the UK but lagging behind in terms of recognition in clinical practice. This meeting was a first step towards addressing the gap and the future looks promising, not only for understanding underlying mechanisms but also for standardising diagnosis and developing beneficial lifecourse interventions.

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