MRC DiMeN Doctoral Training Partnership: Skeletal muscle-blood vessel crosstalk drives muscle pathology during heart failure and diabetes

An ageing global population brings new health challenges. There are increasing incidences of patients with multiple chronic illnesses such as type 2 diabetes (DM) and chronic heart failure (CHF). To meet this challenge our research at the Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, aims to understand how different cells, tissues and organs communicate and how this communication is disrupted by multimorbidity^1-4.

The main symptom for people with heart failure is exercise intolerance. This is linked to loss of muscle mass and quality⁵, which is characterised by impaired muscle mitochondrial metabolism and blood vessel loss^4,6. In multi-morbid patients with both CHF and DM (DMHF) the exercise intolerance, frailty, muscle wasting and metabolic dysfunction are worse⁴ and no pharmacological treatments are known to treat this muscle pathology.

Blood vessel dysfunction, particularly of the endothelium, is common in muscle from both CHF and DM patients⁷. How much endothelial dysfunction contributes to muscle pathology in DMHF is unknown. Reciprocally, how much a muscle pathology induces endothelial impairments is unclear. This project will explore the crosstalk between blood vessels and muscle from patients to understand how this is disrupted in DMHF and to find new therapeutic approaches to DMHF muscle dysfunction.

The postgraduate researcher (PGR) will use multi-omics in collaboration with our industrial partner, Waters Corporation, to characterise the muscle cell and blood vessel endothelial cell secretome (secreted molecules) using a highly characterised clinical population of control, DM, HF and DMHF patients. They will study the physiological relevance of secreted factors using multi-omic analysis of muscle, endothelium and blood plasma from patients with DMHF and correlate with clinical data. The PGR will then culture healthy human muscle and endothelial cells and treat the cells with secretory factors to determine whether they contribute to muscle and blood vessel dysfunction observed in DMHF. The PGR will learn how to design mouse model experiments to determine if treatment of animals with the secretory factors from DMHF muscle and endothelial cells induce DMHF-like muscle pathology.

This project provides multidisciplinary training across physiological, systems, molecular and cell biology and would suit an individual from these or related backgrounds. The PGR will receive training in human primary tissue culture, multi-omics (metabolomics, lipidomics, proteomics) in collaboration with our industrial partner (Waters Corporation), state-of-the-art metabolic techniques including high-resolution mitochondrial respirometry and whole body physiological and metabolic assessments of animal models using indirect calorimetry. The PGR will also receive training in standard laboratory techniques (histology, immunoblotting, RT-qPCR) and have regular contact with practicing clinicians. This project offers a unique opportunity to work with supervisors with distinct expertise (Roberts – Diabetes, Metabolism, Muscle, Interorgan Crosstalk; Bowen – Heart Failure, Muscle, Exercise; Cubbon – Diabetes, Heart Failure, Endothelium, Clinician) to address one of the major consequences of DM and HF multimorbidity, skeletal muscle dysfunction-induced frailty. 

Professor Roberts

Profile: https://medicinehealth.leeds.ac.uk/medicine/staff/713/professor-lee-roberts

Twitter: https://twitter.com/Roberts_Lab

Dr Bowen

Profile: https://biologicalsciences.leeds.ac.uk/school-biomedical-sciences/staff/33/dr-scott-bowen

Twitter: https://twitter.com/LabBowen

Dr Cubbon

Profile: https://medicinehealth.leeds.ac.uk/medicine/staff/248/dr-richard-cubbon

Twitter: https://twitter.com/RicCubbon

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply