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Skeletal muscle as a potential central link between sarcopenia and immune ageing

Primary Supervisor: Dr Niharika A Duggal, Institute of Inflammation and Ageing

Secondary supervisor: Dr Leigh Breen

PhD project title: Skeletal muscle as a potential central link between sarcopenia and immune ageing

University of Registration: University of Birmingham

Project outline:

Background: Ageing is accompanied by sarcopenia and remodelling of the immune system, termed immunesenescence. Skeletal muscle can regulate immunological and inflammatory processes via myokine signalling (IL15, IL7, IL6) and expression of immunomodulatory surface molecules (ICAM1, NKG2L) that regulate cell-cell interactions (NK cell distribution, naïve T cell survival and CD8 T cell homeostasis). Some myokines such as IL7 and IL15 are inversely associated with age. In turn, immune cells infiltrate skeletal muscle and this can be a positive influence as the production of Meteorin-like (MTRL) by macrophages which is important for muscle repair and growth via satellite cell turnover and induction of IGF-1 to aid myogenesis and for inducing an anti-inflammatory phenotype in infiltrating macrophages [6]. With age macrophage function declines and their recruitment to muscle after damage is reduced [7]. These cells also have a tendency to be pro-inflammatory which may increase local cortisol generation and muscle catabolism via activation of 11-βHSD1 [8]. MTRL can also be produced by muscle cells and whether the ability of either these cells or macrophages to produce MTRL declines with age is unknown. Taken together these observations suggest a close interaction between skeletal muscle and the immune system which is likely altered during ageing.

Need for the project: Skeletal muscle outputs, including myokines, might be the central integrators between sarcopenia and immune ageing in an ageing biological system. The proposed project will examine the bidirectional relationship between sarcopenia and immune ageing and the potential mechanisms involved, developing a better understanding of the impact of ageing on the cross-talk between muscle and immune cells.

Aims : 1. To investigate the relationship between sarcopenia, age-associated inflammation and immunesenescence. 2. To investigate the underlying mechanisms.

Experimental plan: Study design: All participants will be assessed for body composition and muscle mass and strength (, hand grip strength, TUG, gait speed) and asked to completed questionnaires (health and wellbeing, SARC-F, diet) . Muscle biopsies and blood samples (40ml) will be collected.

Group1: healthy young participants (non-sarcopenic, aged 18-35 years; n = 30) Group 2: healthy old participants (non-sarcopenic; aged > 60 years, n = 30)

Group 3: Sarcopenic older adults (SMI < 10.75 kg/m2 in men, SMI< 6.75 women; n = 30)

Objective 1 methodology: Deep immune phenotyping of PBMC’s by flow cytometry and immunostaining to establish degree of immunesenescence creating a composite IMM-AGE score. Single cell RNA sequence (scRNA seq) will be used to comprehensively characterise the distribution of different immune cell populations, fibro-adipogenic progenitors and adipocytes in muscle biopsies from healthy young (, healthy non-sarcopenic old and sarcopenic old . Gene expression analysis will enable us to compare intrinsic differences in immune cells, clonal expansion profiles, DNA repair genes expressions (ATM), expression of inflammation related gene targets (IL6, TNF, sTNFR1, TLR4), anti-inflammatory (IL10, IGF1), senescence markers

(p16Ink4A) myokines (IL7, IL5, MTRL), immune modulatory molecules (ICAM1, PD1, NKG2DL), genes regulating muscle turnover (mTOR, IGF-1, MuRF1, MAFBx) and unbiasedly assess additional potential mechanisms between the four cohorts.

Machine learning and mathematical modelling approaches, such as SIMON (collaboration with University of Oxford) will be used to determine relationships between the immune and muscle cell components, including which cells are likely interacting determined by surface receptor expression.

Objective 2 methodology:

To try and determine mechanism involved and go beyond associations, conditioned medium collected from low frequency stimulated differentiated human myotubes isolated from healthy young, old and sarcopenic old individuals will be applied to immune cells followed by transcriptome analysis (global mRNA sequencing).

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:

  • Physiological testing on participants
  • Cell culture
  • Flow cytometry
  • Single cell RNA sequencing
  • Genome profiling
  • Mathematical modelling using machine learning

Contact: Dr Niharika A Duggal, University of Birmingham