Exercise 'prehabilitation': A novel intervention to protect against disuse-induced muscle atrophy and sarcopenia in the old

Skeletal muscle mass plays an essential role in activities of daily living and regulation of metabolic health. Ageing is associated with a progressive decline in skeletal muscle mass (sarcopenia) that compromises tasks of daily living, metabolic health and increases the risk of falls, fractures and mortality. The healthcare costs associated with treating age-related musculoskeletal decline are vast, and continue to grow with our expanding ageing population. Of concern is that ~30% of those aged 75-84 years suffer from sarcopenia. Thus, interventions to reduce the progression of age-related muscle wasting will improve the quality of life in older individuals and have a profound impact on healthcare expenditure. To place this into context, a 10% reduction in the incidence of sarcopenia would result in an enormous reduction in healthcare expenditure associated with muscle deterioration (estimated annual cost to the NHS of £5.7 billion).

Ageing is associated with an impairment in the normally healthy muscle metabolic response to nutrition, a phenomenon that has been termed 'anabolic resistance'. Age-related muscle anabolic resistance to nutrition may underpin the progression of sarcopenia. The root-cause of age-related muscle anabolic resistance is complex, but may be partly related to periods of disuse and inactivity, which occur with increasing frequency in older individuals. Specifically, the dysregulation in muscle metabolism that occurs during successive periods of short-term disuse and inactivity may accumulate over time to form the characteristic muscle anabolic resistance of ageing. Alarmingly, muscle deterioration occurs soon after the onset of disuse in older adults. This is important as the average length of hospital stay in older individuals is 5-6 days. Therefore, we believe a focus on maintaining healthy muscle metabolism during short-term disuse events is an important research priority in the fight against sarcopenia.

Resistance exercise is a potent stimulus for muscle anabolism and can offset muscle loss during disuse in older individuals. However, older individuals are typically unable (or unwilling) to perform strenuous physical activities during disuse events. Interestingly, we recently observed that resistance exercise can restore the muscle anabolic response to nutrition in older individuals, and this enhanced metabolic response persists for several days after exercise completion (after older individuals have returned to a sedentary lifestyle). Therefore, resistance exercise prior to short-term disuse (termed 'prehabilitation') may protect muscle mass, strength and metabolic function in older individuals, with important implications for the progression sarcopenia and promotion of healthy ageing.

In the proposed project, we will investigate whether resistance exercise prehabilitation protects against muscle and strength loss during short-term disuse in older individuals. A cohort of healthy older individuals will complete single-leg exercise prehabilitation (for comparison with the untrained control leg), consisting of either single or multiple bouts of resistance exercise. Immediately following exercise prehabilitation, participants will undergo 5 days of strict bed-rest. Detailed assessment of muscle size, architecture, and strength will conducted prior-to and following bed-rest. Furthermore, we will use sophisticated measurement techniques to understand the precise mechanisms that underpin alterations in muscle size and strength during short-term bed rest, and whether adaptations in these mechanisms can explain the protective effects of exercise prehabilitation on muscle health. Ultimately, we hope to demonstrate that exercise prehabilitation is an effective means of preventing muscle deterioration during short-term disuse in older individuals, which will ultimately slow the trajectory of sarcopenia and promote healthy, independent ageing in a diverse and expanding older population.

The accumulation of disuse events in older individuals may underpin chronic impairments in muscle protein metabolism thought to be a primary cause of sarcopenia. Therefore, interventions to offset muscle deterioration during disuse events in older individuals may slow the progression of sarcopenia, improve quality of life and reduce associated healthcare expenditure. Resistance exercise is a potent stimulus to for muscle anabolism and can offset muscle atrophy and strength loss during disuse. However, implementing vigorous physical activity interventions during disuse events in the old may be impractical. In the proposed study, we will investigate whether resistance exercise prior to short-term bed rest ('prehabilitation') can offset muscle atrophy and metabolic dysregulation in older males. Using a parallel-group, within-subject control study design, we will recruit 24 older individuals (aged 65-80 yrs) to the study. Over a 7-day lead in phase, participants will perform one bout (SINGLE; n=12) or multiple bouts (MULTI; n=12) of moderate-intensity single-leg resistance exercise (the other leg will act as an untrained control). Immediately after the exercise prehabilitation phase, participants will undergo 5 consecutive days of strict bed-rest, previously shown to induce muscle and strength loss. Quadriceps volume, architectural properties and strength will be comprehensively assessed by magnetic resonance imaging, ultrasound and dynamometry in trained and untrained control legs. Serial muscle biopsies will be combined with oral D2O tracer consumption to assess long-term rates of muscle protein synthesis and markers of muscle protein breakdown during prehabilitation and bed-rest phases. An acute stable isotope tracer infusion will be used to determine whether resistance exercise prehabilitation protects against muscle and strength loss during short-term bed rest by enhancing the acute muscle protein synthetic response to nutrition compared with the untrained leg

The long-term impact of this research could be substantial. The proposed project has the potential to augment the nation's health through significantly enhancing quality of life in older individuals, whilst reducing the healthcare costs associated with disease burden in an ageing population.

This project will determine the efficacy of exercise prehabilitation to counteract muscle deterioration during short-term disuse in older individuals by targeting the underlying metabolic and molecular mechanisms. We believe that the development of effective strategies to counteract disuse-induced muscle deterioration in older individuals will have profound implications for slowing the development of sarcopenia, thereby closing the gap between lifespan and health-span to promote healthy ageing. The benefits of resistance exercise for muscle hypertrophy and strength in young and old have been clearly demonstrated. Likewise, resistance exercise performed during a period of disuse effectively offsets muscle deterioration. However, the feasibility of implementing resistance exercise during 'real-world' disuse events in older individuals is questionable, particularly as the old are often unable or unwilling to perform physical activity in a clinical setting. The influence of exercise prior to disuse events (prehabilitation) on muscle mass, strength and function in older individuals is poorly understood, but offers a novel and feasible means of alleviating age-related muscle deterioration during anticipated disuse events, whilst improving other related health outcomes. For example, over 140,000 elective knee and hip replacement surgeries are performed in the UK annually (mostly in those aged 65 and over), leading to hospitalization and an inevitable decline in physical function and mobility. Thus, older individuals undergoing such anticipated disuse events would be ideally placed to benefit from the muscle protective effects of exercise prehabilitation.

Sarcopenia is the result of complex interaction of multiple underlying pathologies, rather than a disease-state per se. Therefore, the development of interventions to treat sarcopenia is complex. Irrespective of the underlying genetic and hormonal factors that underpin sarcopenia, lifestyle factors (physical inactivity/disuse) exacerbate this process, leading to significant impairments in functional ability and metabolic health that reduce quality of life and increase mortality risk. Estimates suggest that ~30% of those aged 75-84 years suffer from sarcopenia, which is alarming when one considers that the number of older individuals aged 80 years and over will increase by ~3-fold between now and 2050. As a result, the enormous healthcare costs of treating sarcopenia and other-related conditions (i.e. falls. fractures) will continue to increase with an ageing population. We believe this project has the capacity to profoundly influence national and global policy recommendations on the promotion of healthy ageing, particularly in a the context of a clinical setting. Through influencing healthcare policy, the proposed work offers considerable clinical and socio-economic impact. Currently, there is clear recognition of the need to develop interventions to counteract muscle loss and extend the health-span in an ageing population. In this regard, the development of exercise prehabilitation as tool to offset disuse-induced muscle deterioration in older individuals will directly address this need, through translation into routine clinical care by health professionals. Given the clear outcomes of the proposed project, an optimistic estimate for the time required for the translation of this work into a safe and economic treatment would be in the order of 3-5 years based on the likely need for development of individually tailored exercise prehabilitation strategies.