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Does immune system deterioration and adipose tissue dysfunction influence skeletal muscle mass in older adults and is there a restorative role for exercise?
Secondary Supervisor(s): Professor Leigh Breen
University of Registration: University of Birmingham
BBSRC Research Themes: Understanding the Rules of Life (Immunology)
Project Outline
In the UK, 10 million people are 65 years or older, rising to 19 million by 2050. Ageing is characterised by immune system deterioration, inflammation and declining skeletal muscle mass. In addition, even among older adults who are not obese, there is a gradual accumulation of adipose tissue, which becomes dysfunctional. Previously we recruited 12 Young (27±4y, BMI 24.5±1.4 kg/m2) and 12 Old non-obese people (66±5y, BMI 24.8±1.4 kg/m2) [1]. After matching for adiposity, older people had double the number of most inflammatory immune cells in their adipose tissue – cells that are implicated in an ageing immune system. In addition, adipose tissue cultures from older people exhibited high inflammatory molecule secretion. Although systemic inflammation is mechanistically implicated in skeletal muscle decline with ageing, it is unknown whether inflammatory secretions from adipose tissue “condition” human serum, contributing to systemic inflammation and therefore driving skeletal muscle decline. We have shown by culturing C2C12 myotubes with serum-conditioned media from non-obese Young (27+3y, BMI 26.1±3.1 kg/m2, n=4) and Old people (73+1y, BMI 24.0±3.8 kg/m2, n=4) that myotube diameter was much lower after treatment with Old serum, characterised by high levels of inflammatory molecules [2]. The source of this systemic inflammation is unproven, but the proposed work will establish the role and interconnectivity of two likely processes – immune system deterioration and adipose tissue dysfunction – in driving skeletal muscle decline with ageing.
Objectives
Establish whether immune system deterioration and adipose tissue dysfunction with ageing influence skeletal muscle mass and function and whether exercise can reverse these effects.
HYPOTHESIS 1: Skeletal muscle properties in-vitro will be impaired more when cultured with serum, adipose tissue secretions, and stimulated blood secretions from older adults compared with younger adults.
HYPOTHESIS 2: Skeletal muscle properties in-vitro will be impaired less when cultured with serum, adipose tissue secretions, and stimulated blood secretions collected after a 3 month exercise/diet intervention that improves adipose tissue and skeletal muscle profiles, compared with pre-intervention.
Details of Potential Methods and Time Plan
WORK PACKAGE 1: Observational study: young (n=20) vs. old (n=20).
WORK PACKAGE 2: Randomised-controlled-trial: 3 months exercise/diet vs. control (old n=20 per group).
Blood, subcutaneous adipose tissue and skeletal muscle will be sampled and body composition and fitness (including in vivo muscle function) assessed. Serum, supernatant from stimulated blood cultures (e.g., stimulants: mitogens, virus antigens) or supernatant from adipose tissue cultures will be incubated with mouse-C2C12 and human-LHCN-M2 muscle cell lines. Properties assessed: immunohistochemistry (myotube diameter, nuclei), immunoblotting: (protein synthesis - puromycin incorporation, intracellular signalling). Blood/adipose/muscle immune cell phenotypes/function will be assessed with multi-parameter flow cytometry.
Months 0-6: WP1 ethics application, method development, training.
Months 6-24: WP1: recruits 2-3 participants/month – continuous data analysis.
Months 24-27: WP2: design with stakeholder development, ethics application.
Months 27-45: WP2: 3 month intervention starts for 3 participants per month (15 months of recruitment)
Months 45-48: Finalise analyses/thesis.
References
[1] Trim W, Walhin JP, Koumanov F, Bouloumie A, Lindsay M, Travers R, Turner JE & Thompson D. Divergent immunometabolic changes in adipose tissue and skeletal muscle with ageing in healthy humans. The Journal of Physiology 2022, 600 (4) 921-947.
[2] Allen SL, Marshall RN, Edwards SJ, Lord JM, Lavery GG, Breen L. The effect of young and old ex vivo human serum on cellular protein synthesis and growth in an in vitro model of aging. American Journal of Physiology Cell Physiology. 2021 Jul 1;321.