Are mechanisms of skeletal muscle atrophy simply the reverse of muscle hypertrophy across age? A multi-omics approach

As we get older, our muscles become smaller and weaker, making it harder to carry out everyday tasks. It is therefore advantageous to take part in activities that make our muscles bigger. Understanding how muscles get smaller and bigger during ageing is really important to keeping our muscles and bodies healthy. Even though this is clearly an important issue, we still do not know the molecules within our bodies that cause these changes in muscle size. Although muscle loss is the opposite to muscle growth, evidence shows that at least some of the molecules that cause muscle loss are not same as the molecules that cause muscle growth. If we can understand more about these molecules, we may be able to find new treatments to stop muscle loss and help muscle growth in ageing people, which would have a major impact on the quality of life for millions of older (> 65 years of age) adults. This project will use experiments in human volunteers to measure the effects of muscle loss and muscle growth on; the ability of muscles to function/ move, the size of the muscle, the ability of the muscle cells to breath and the molecules within the muscle. Then, advanced computer software will be used to assess thousands of the molecules within the body and choose which ones might be important for changes in muscle function and muscle loss/ growth. To try and understand in more detail if these identified molecules are important to muscle health, they will be tested in lab-based experiments using cells taken from human muscles. By doing so, we can make the cell stop producing the molecule of interest to see what happens to muscle health, which is not possible to do in human experiments. This project will provide a better understanding of how we grow and lose muscle and how this is affected as we get older, which will be extremely valuable in the development of treatments to improve muscle health during ageing.

Ageing is associated with the loss of muscle mass (sarcopenia), where inducing muscle growth (i.e. hypertrophy) is the key goal of therapeutic interventions that combat muscle loss (i.e. atrophy). Elucidating the mechanisms underlying atrophy and hypertrophy across ages is therefore crucial to maintaining a healthy skeletal muscle mass across the lifecourse, which is essential to preserving locomotory function and whole-body metabolic health. Nonetheless, whether the mechanisms of atrophy are divergent or simply the reverse of hypertrophy remains a fundamental, yet unanswered biological question. This fellowship will detail the functional (e.g. muscle strength), morphological (e.g. muscle fascicle length and cross-sectional area), metabolic and targeted and untargeted molecular responses to atrophic and hypertrophic stimuli in young and older adults. Computational modelling, specifically differential and network analysis, will be applied to omic data sets to determine individual genes/ metabolites that are differentially expressed, biologically-related groups of genes/ metabolites that are co-expressed and the interactions between genes and metabolites (i.e. multi-omics), as a function of age and (lack of) mechanical stimulus (atrophy/ hypertrophy). Key candidate gene targets identified from the bioinformatics analysis will be reverse-translated into human primary skeletal muscle cells to experimentally validate network-predicted mechanisms of atrophy and hypertrophy, as a function of age. This will provide a significant enhancement in the knowledge needed for the development of therapeutic interventions aimed at offsetting muscle atrophy and/ or promoting muscle hypertrophy across the lifecourse.

This research has the potential to identify novel regulators of skeletal muscle atrophy and hypertrophy in young and older adults. This will be a significant enhancement in the knowledge needed for the development of therapeutic interventions aimed at offsetting muscle atrophy and/ or promoting muscle hypertrophy across the lifecourse. The impacts of this work should be realised over short (<3 years) and longer (>3 years term) and may have a positive impact on a number of important beneficiaries expanded on below. Briefly: (1) patients and general public; (2) public engagement groups; (3) clinicians and allied health professionals; (4) industry; (5) policy makers; (6) students, and (7) scientific community.

(1) Patients and general public: Age-related muscle loss reduces independence and significantly reduces one's quality of life. This project will identify the precise molecular regulators of muscle atrophy and hypertrophy, which is critical to developing interventions that may offset muscle atrophy and/ or promote muscle hypertrophy. As such, this project stands to have significant medium- to long-term benefits for the increasingly ageing UK population.
(2) Public engagement groups: The potential to know the mechanisms underpinning age-related muscle decline is generally relatable and will engage public interest and raise awareness of the fellow's research profile, UoE and the MRC.
(3) Clinicians and allied health professionals: Current interventions against age-related muscle atrophy are not fully effective. Identifying the precise molecular regulators of muscle atrophy and hypertrophy may alter the way health across the lifespan is managed. For example, if progression of muscle atrophy can be attenuated in during ageing or in atrophy-promoting situations (e.g. hospital stays), then clinical practise may be adapted accordingly.
(4) Industry: identifying potential avenues for therapeutic intervention against muscle atrophy/ for muscle hypertrophy may provide industry (e.g. nutritional/pharmaceutical companies) with promising new candidates for drug/supplement development against ageing health decline, which could lead to future significant research income.
(5) Policy makers: understanding the mechanisms regulating muscle atrophy and muscle hypertrophy may challenge current government guidelines surrounding the maintenance of muscle health during ageing (e.g. exercise prescription guidelines).
(6) Students: the opportunity to combine expertise in metabolic/ molecular physiology with computation modelling to answer fundamental biological questions will form the foundations of my future independent research group. As such, the longer-term impact of this research is to encourage and develop upcoming researchers to have this unique skill set.
(7) Scientific community: please see "academic beneficiaries"