Are mechanisms of skeletal muscle atrophy simply the reverse of muscle hypertrophy across age? A multi-omics approach
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Sport and Health Sciences
Abstract
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.
Technical Summary
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.
Planned Impact
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"
(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"
People |
ORCID iD |
Colleen Deane (Principal Investigator / Fellow) |
Publications
Bass JJ
(2021)
The mechanisms of skeletal muscle atrophy in response to transient knockdown of the vitamin D receptor in vivo.
in The Journal of physiology
Bass JJ
(2020)
Overexpression of the vitamin D receptor (VDR) induces skeletal muscle hypertrophy.
in Molecular metabolism
Baumann CW
(2023)
Adaptability to eccentric exercise training is diminished with age in female mice.
in Journal of applied physiology (Bethesda, Md. : 1985)
Deane CS
(2021)
Transcriptomic meta-analysis of disuse muscle atrophy vs. resistance exercise-induced hypertrophy in young and older humans.
in Journal of cachexia, sarcopenia and muscle
Deane CS
(2022)
Curcumin Enhances Fed-State Muscle Microvascular Perfusion but Not Leg Glucose Uptake in Older Adults.
in Nutrients
Deane CS
(2020)
Animal, Plant, Collagen and Blended Dietary Proteins: Effects on Musculoskeletal Outcomes.
in Nutrients
Deane CS
(2020)
Challenges and practical recommendations for successfully recruiting inactive, statin-free older adults to clinical trials.
in BMC research notes
Deane CS
(2021)
Exploring the impact of COVID-19 on the willingness of older adults to participate in physiology research: views from past and potential volunteers.
in Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme
Description | MyAge - Proof of Concept |
Amount | £6,600 (GBP) |
Organisation | United Kingdom Research and Innovation |
Sector | Public |
Country | United Kingdom |
Start | 11/2022 |
End | 05/2023 |
Description | MyAge Pump Prime |
Amount | £750 (GBP) |
Organisation | United Kingdom Research and Innovation |
Sector | Public |
Country | United Kingdom |
Start | 05/2022 |
End | 09/2022 |
Description | TREE Public Engagement with Research, Wellcome Trust Institutional Strategic Support Fund |
Amount | £3,401 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2020 |
End | 10/2020 |
Description | University of Exeter Early Career Researcher Network Funding |
Amount | £8,000 (GBP) |
Organisation | University of Exeter |
Sector | Academic/University |
Country | United Kingdom |
Start | 04/2022 |
End | 08/2022 |
Description | Atrophy/Hypertrophy Systematic Review |
Organisation | Ritsumeikan University |
Country | Japan |
Sector | Academic/University |
PI Contribution | This collaboration involves producing a systematic review. I have performed the systematic searches, filtered the searches, I will also pull the data from the papers for meta-analysis. |
Collaborator Contribution | They have been writing sections of the manuscript for the systematic review. |
Impact | This is multi-disciplinary, brining together clinicians and physiologists. No outputs yet, the systematic review is still in progress. |
Start Year | 2020 |
Description | Atrophy/Hypertrophy Systematic Review |
Organisation | University of Nottingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This collaboration involves producing a systematic review. I have performed the systematic searches, filtered the searches, I will also pull the data from the papers for meta-analysis. |
Collaborator Contribution | They have been writing sections of the manuscript for the systematic review. |
Impact | This is multi-disciplinary, brining together clinicians and physiologists. No outputs yet, the systematic review is still in progress. |
Start Year | 2020 |
Description | ESA Space OMIC Topical Team |
Organisation | European Space Agency |
Country | France |
Sector | Public |
PI Contribution | I was invited to be a contributing member of the ESA OMIC Topic Team. I bring my expertise in physiology. I have already contributed to this topical team by doing an oral presentation on behalf of the Topical Team at an internal conference, contributed to a published Letter and I am currently leading a historical review. |
Collaborator Contribution | The ESA OMIC topical team has many members which bring a wealth of expertise, ideas and collaborations. The aim of the topical team is to help accelerate the role of the EU in space omics. |
Impact | - Two conference proceedings (both logged in Publications): 1. Deane, C. S., Gabel, A., Villacampa, A., Manzano, A., Madrigal, P., Weging, S., Morris-Paterson, T., Cahill, T., Carnero-Diaz, E., Medina, F. J., Hardiman, G., Grosse, I., Harridge, S., Szewczyk, N., Giacomello, S., Bezdan, D., da Silveira, W. A. & Herranz, R. (2020) 'A ESA space omics topical team to help expand and accelerate space omics in Europe, American Society of Gravitation Space Research. 2. da Silveira, W. A., Deane, C. S., Villacampa, A., Gabel, A., Weging, S., Cahill, T., Madrigal, P., Morris-Paterson, T., Harridge, S., Giacomello, S., Medina, F. J., Carnero-Diaz, E., Grosse, I., Etheridge, T., Hardiman, G., Bezdan, D., Szewczyk, N., & Herranz, R. (2021) 'Results and opportunities from the ESA Space Omics topical team: towards an integrated ESA/NASA-omics database for spaceflight and ground facilities experiments', Committee on Space Research. - Publication (logged in Publications): Madrigal, P., Gabel, A., Villacampa, A., Manzano, A., Deane, C. S., Bezdan, D., Carnero-Diaz, E., Medina, F. J., Hardiman, G., Grosse, I., Szewczyk, N., Weging, S., Giacomello, S., Harridge, S., Morris-Paterson, T., Cahill, T., da Silveira, W. A. & Herranz, R. (2020) 'Revamping space-omics in Europe', Cell Systems, epub ahead of print. |
Start Year | 2020 |
Description | Immob+PRO RNA Seq |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | I will cover the cost of RNA sequencing on the biological samples and perform the subsequent bioinformatic analysis, data interpretation and write up. |
Collaborator Contribution | provided biological samples |
Impact | This is multi-disciplinary bringing together physiologists and bioinformaticians. No outputs yet. Samples are being analysed. |
Start Year | 2021 |
Description | Rodent RNAseq |
Organisation | Ohio University |
Country | United States |
Sector | Academic/University |
PI Contribution | I will cover the cost of RNA sequencing on the biological samples and perform the subsequent bioinformatic analysis and data interpretation. |
Collaborator Contribution | Dr Cory Baumann (Ohio University) will provide animal tissue from experiments to under RNA sequencing. Prof Nathaniel Szewczyk (Ohio University) and Dr Timothy Etheridge (University of Exeter) have provided the collaborative link and will provide their expertise and intellectual input. |
Impact | None yet. Samples are currently in shipment to destination where they will undergo RNA sequencing. |
Start Year | 2020 |
Description | Worms in space review |
Organisation | Ohio University |
Country | United States |
Sector | Academic/University |
PI Contribution | This collaboration involves producing a review of worm and omics works in the context of altered gravity. My role is to plan and write most of the review. I will also oversee the input from a medic (Ohio University). |
Collaborator Contribution | Prof Nathaniel Szewczyk (Ohio University) initiated the review along with Dr Timothy Etheridge (University of Exeter). They will both have input into the drafts. Amanda Scott (Ohio University) is a medic who is contributing to the writing of the review. |
Impact | This is multi-disciplinary, bringing together physiologists and medics. No outputs yet, review is still in progress. |
Start Year | 2021 |
Description | BBC radio news interview for space week |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Interview with BBC radio Devon to celebrate space week. Discussed the MME, impacts of spaceflight on the body, the ISS, ways to the moon and influencing and engaging future generations to be aware of spaceflight. |
Year(s) Of Engagement Activity | 2019 |
Description | Creating a Life on Mars |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Roughly 60-80 secondary school students and their teachers attended the 'Creating a Life on Mars' event (4wardfutures). The day consisted of talking about career paths into the space sector, presenting the molecular muscle experiment, discussing astronaut selection, and interacting with the students to help them plan and build a landscape of Mars. Discussions occurred between students, scientists, engineers, and programme managers. Several students expressed interest in pursuing STEM degrees at University and several students expressed thanks for the our help during the event. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.calom.space/life-on-mars |
Description | Huawei + Pint of Science docu-series |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I filmed 13 3-5 minutes videos on my research profile as part of a collaboration with Huawei and Pint of Science. My theme was 'Worms in space for health on earth', and the videos covered the following; why muscle is an important organ, what happens to the body in space, why worms are a good model for research, what worms can teach us about health on earth, what the Molecular Muscle Experiment was and how it was conducted, what the Molecular Muscle Experiment 2 is, how we can translate findings in worms into humans, clinical trials in humans and how they are conducted, how are human muscle samples analysed, maths for muscle health, how to get involved in space science. These videos are currently being edited prior to release in the Chinese and international market (released via Huawei's media channels including YouTube and TikTok) |
Year(s) Of Engagement Activity | 2020 |
Description | President's Lecture 2019, The Physiological Society |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | ~ 300 adults and children attended The Presidents Lecture at the Royal Institution, run by The Physiological Society. This event included a talk by an astronaut (Jim Pawelczyk), followed by 2.5 hours of hands-on activities to inspire children about space and physiology. We were one of the chosen hands-on activities, which included looking at healthy and "space" C. elegans, handling hardware that has been to space and discussing worms as a model for biology and biological changes in spaceflight. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.physoc.org/events/presidents-lecture-2019/ |
Description | Sidmouth Science Festival 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Attended Sidmouth Science Festival 2019 and interacted with members of the general public. Activities included looking at normal and mutant worms, observing materials (i.e. worm bags) that have been returned from space and talking about science and spaceflight. The general public were enthusiastic and very engaged with the activities. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.sidmouthsciencefestival.org/festival |
Description | Space physiology animation |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Scientific advisor and narrator of The Physiological Society animation, "what happens to our body in space?", which is available on YouTube. |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.youtube.com/watch?v=y7rDrAKRqjo |
Description | Sport + Health Sciences Conference 2020 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Postgraduate students |
Results and Impact | I organised and ran the SHS Conference 2020. The purpose of this conference is to being together undergraduates, postgraduates, early career researchers and academics to present and discuss research findings in a constructive environment. Feedback from these events has evidence that collaborations have been made and result interpretations have been amended. |
Year(s) Of Engagement Activity | 2020 |
Description | Student Experiment Spaceflight Programme (SSEP) proposal |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Schools |
Results and Impact | Gave advice to 9th and 10th grade students at Chandler Park Academy High School, in Harper Woods, MI (US) on research question/s and experimental design for their SSEP proposal for the SSEP Mission 14 to the International Space Station. This proposal was submitted on 1/11/19. |
Year(s) Of Engagement Activity | 2019 |
URL | http://ssep.ncesse.org |
Description | The Physiological Society Impact Report |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Wrote a small piece for The Physiological Societie's Impact Report, reflecting on our "Worms in Space" activity at the Presidents Lecture. No impacts know at this stage. |
Year(s) Of Engagement Activity | 2020 |