Structural and metabolic determinants of sarcopenia and efficacy of concentric vs. eccentric exercise training: a novel temporospatial approach

Most people will have noticed that with age people become frail. This is principally due to the wasting of skeletal muscle (a process called "sarcopenia"). Skeletal muscle wasting occurs not only with older age but also with a large number of common illnesses: trauma, burn injury, diabetes, cancer, heart failure, renal failure, Alzheimer's disease, and arthritis (to name but a few). Crucially, in these cases, muscle wasting is more than just a symptom of weakness and poor functional capacity. Muscle wasting exposes us to an increased risk of falls and fractures, which often lead to death within a year in the aged. Thus, muscle wasting occurring in disease and with age impacts on quality of life, independence, morbidity and mortality and represents a major UK health problem. However, we currently understand little about the processes that regulate sarcopenia in humans. The best-known means by which to counter muscle wasting occurring in older age is exercise. For example, if one were to look at a body builder they would notice the gross musculature gained (called "hypertrophy") from lifting weights. While muscle growth on this scale is not possible in older age, a degree of muscle growth and functional improvement can be achieved. Finding optimal exercise strategies with which to counteract sarcopenia is therefore an important goal.

In the current proposal we have developed a novel strategy to explore human sarcopenia and exercise strategies with which to offset it. We have recently found that sarcopenia manifests in two "spatially" different ways. Sarcopenic muscles display wasting due to reductions both in muscle "length " at the muscle end, and muscle "width" along the mid-section. Therefore, our first goal is to study older and younger people over a period of 2 months to define the process(es) responsible for loss of muscle length AND width in sarcopenia. To achieve this we will provide young and older volunteers with daily drinks of "labelled water" from which we will be able to track longitudinal changes in important aspects in the building processes of muscle (by taking intermittent muscle samples from the muscle middle and end) over this entire period. This approach will explain why human sarcopenia is spatially distinct.

Secondly, we propose to assess excercise interventions for reversing human sarcopenia. Conventional resistance exercise is composed of both lengthening and shortening muscle contractions (touch your shoulder and imagine lowering down a dumbbell (lengthening) and then lifting it again (shortening). Intriguingly, when exposing individuals to either exclusive lengthening or shortening exercise training we have found that lengthening exercise increases muscle length and shortening exercise increases muscle width. Herein we propose to trial the efficacy of lengthening and shortening contractions in counteracting spatial differences we have identified in sarcopenia while also studying the mechanisms underlying why these contractions work the way they do. To achieve this we will provide young and older volunteers with daily drinks of "labelled water" during either lengthening or shortening contraction training after which we will be able to track longitudinal changes in important aspects in the building processes of muscle (by taking intermittent muscle samples from the muscle middle and end) over this entire period in youth and ageing.

This project will have significant, perhaps groundbreaking, implications for our understanding of the control of skeletal muscle size in humans, particularly in relation to the problem of sarcopenia.

We propose to take a human systems physiology approach that couples whole body functional, whole tissue anatomic, and sub-cellular molecular and metabolic measures to address the molecular basis of sarcopenia, the molecular basis of exercise induced muscle growth, and optimal strategies with which to use exercise to counteract sarcopenia. We have shown that sarcopenia (viewed by DXA/ MRI) is due to specific architectural changes on an individual muscle level, viz: loss of sarcomeres in series and sarcomeres in parallel (by ultrasound). To determine the basis of these changes, we will sample tissue at the muscle mid-belly (loss of sarcomeres in parallel) and close to the distal aponeurosis (loss of sarcomeres in series). Using a new tracer (D2O) approach we will measuring turnover of muscle sub-fractions (e.g. myofibrils, myoplasm, mitochondria, nuclei [satellite cells]) and correlate these with standard measures of anabolic signalling (e.g. detection of phosphorylation events in these pathways). Data from these measures will then be correlated with tissue level changes and defined by comparison to a younger group to seek age x spatial architecture/ spatial metabolic differences such to identify the dynamic metabolic underlying sarcopenia. Next, we will determine the longitudinal and spatially distinct alterations in architecture, signalling, and metabolism (as above) in response to concentric (CON) vs. eccentric (ECC) contraction by comparison to a young population to seek contraction x age x spatial architecture/ spatial metabolic differences. This will inform on (i) dynamic processes regulating distinct spatial adaptations to ECC/CON and (ii) the efficacy of ECC vs. CON in reversing spatially distinct aspects of sarcopenia. Lastly, we will measure the effect of ECC vs. CON in functional terms (e.g. strength gains, improved gait, improved balance, etc.) to determine if ECC or CON is more effective at combating the functional consequences of sarcopenia.

In addition to academic beneficiaries we believe this work will benefit, the wider public, the commercial private sector, charities, and the staff working on the project. Academic beneficiaries will be the wider muscle community as we will provide innovative knowledge on the mechanisms of muscle growth in response to different modalities of mechanical loading, the causes of the blunted anabolic response to resistive training in old age, and proof of concept of the efficacy of repeated, submaximal muscular exercise for combating sarcopenia and weakness in old age. Additionally, we will develop a new resource for use by other scientists in the field. Our muscle protein synthesis (MPS) determination by D2O method provides an unprecedented method for studying the temporal and sub-cellular variations in muscle protein metabolism based on chronic rate determinations of MP; many groups will likely use this approach for mechanistic research into hypertrophy and sarcopenia. The wider public will benefit from this work in the form of improved diagnosis and treatment of sarcopenia, ultimately (it is hoped) decreasing public healthcare expenditure. We will directly examine the type, modality and impact of muscle loading exercise regime most efficacious for treating sarcopenia. Within 3-5 years this could reduce the public healthcare expenditure for conditions associated with declining muscle health (for example in this case the aged) though reducing economic burden of sarcopenia and perhaps to wider prevalent conditions associated with muscle atrophy i.e. cancer, type II Diabetes. Even more broadly all sectors of the UK could benefit from increased productivity as the result of decreased loss of work days due to muscle problems. Importantly, as we are members of a new MRC/Arthritis Research UK Centre for Musculoskeletal Ageing Research we are uniquely positioned to conduct BBSRC funded basic research and interact with those engaged in seeking treatments for the decline of muscle with age. If exercise proves effective, we can therefore start the translational process as soon as the end of the second year of this project and demonstrate true cross council prioritization of muscle aging research. The commercial private sector will benefit in the development and commercialisation of innovative training contraptions targeted at restoring muscle mass of older individuals. These impacts will be felt within the third year as we present and publish our results of these exercise interventions. Charities will also benefit in much the same way, particularly those charities that support increased quality of life in individuals with problems that involve musculoskeletal frailty, loss of mobility and increased risk of falls (for example: Research into Aging) and Arthritis Research UK who is committed to reducing decline of the entire musculoskeletal system with age. Lastly, the staff working on this project will benefit in two ways. The post-doctoral researcher will gain training in in vivo protein metabolism assessment using this innovative D2O methodology, molecular biology, muscle ultrasound and muscle function, and in the physiological awareness of sarcopenia. The appointed technician will gain unique experience running this new method of assessment of human protein synthesis, thereby strengthen his/her skill-set. Both of these types of professional development will aid in their ability to seek further employment, with additional training in project management being the most transferable skill they will continue to develop. These impacts will be felt within the first year and fully realized in 2-4 years.