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Uncovering the mechanisms of skeletal muscle cellular dysfunction in heart failure patients with diabetes


Project Description

Heart failure (HF) is characterised by exercise intolerance and high mortality – both of which are significantly exacerbated in patients with concomitant type 2 diabetes (DHF). However, that cardiac dysfunction remains similar between HF and DHF patients suggests peripheral, non-cardiac mechanisms may be playing a key role in the DHF phenotype. We have recently collected preliminary data that suggests skeletal muscle mitochondrial dysfunction is playing a contributory role. This project, therefore, aims to better understand the broad cellular mechanisms that may be inducing a skeletal muscle-specific myopathy in patients with DHF compared to HF alone – a question that remains to be answered. Working as part of vibrant translational and multidisciplinary team, the successful candidate will integrate the basic and clinical sciences. Training will be provided in lab-bench skills by the primary supervisor (Dr Scott Bowen) in order to perform relevant molecular and cellular analyses on muscle biopsies from patients. Cellular pathways to be targeted will include mitochondrial dynamics and the fibre size-sarcomeric signalling axis. Histological techniques to assess muscle morphology will be used in addition to Western Blot and RT-PCR to determine protein and gene expression in order to answer the project’s main aims. Additional cell-based experiments will be performed where necessary to tease out cause-effect mechanisms related, for example, to reactive oxygen species and inflammatory cytokines, with potential for subsequent work using animal-based disease models. Furthermore, under the guidance of consultant cardiologist and co-supervisor Dr Klaus Witte, the candidate will have the opportunity to gain experience in the clinical setting through patient recruitment, clinical exercise testing, cardiac imaging, and potential therapeutic interventions.

Funding Notes

We are seeking PhD applicants with the skills and enthusiasm to undertake demonstrating with our Sports and Exercise Sciences undergraduate cohorts. The successful candidate will undertake 120-250 hours of teaching per year alongside their PhD research. You should hold (or be expecting) at least a UK upper second class honours, in a relevant discipline and should also have an interest in teaching.
The studentship is open to UK or EU candidates and will provide fees at UK/EU level plus a stipend of £14,777 for 4 years (subject to progress).

References

Bowen TS, Adams V, Werner S, Fischer T, Vinke P (PhD student), Brogger MN, Mangner N, Linke A, Gasch A, Labeit D, Labeit S. Small-molecule mediated knock-down of the E3 ligase MuRF1 attenuates skeletal muscle atrophy and dysfunction in cardiac cachexia. J Cachexia Sarcopenia Muscle.10.1002/jcsm.12233, 2017.

Bowen TS, Eisenkolb S (PhD student), Drobner J (PhD student), Fischer T, Werner S, Linke A, Mangner N, Schuler G, Adams V. High-intensity interval training prevents oxidant-mediated diaphragm muscle weakness in hypertensive mice. FASEB J. 31(1):60-71, 2017.

Mangner N, Bowen TS, Werner S, Fischer T, Kullnick Y, Oberbach A, Linke A, Steil L, Schuler G, Adams V.Exercise Training Prevents Diaphragm Contractile Dysfunction in Heart Failure. Med Sci Sports Exerc. Nov;48(11):2118-2124. 2016

Bowen TS, Rolim NPL, Fischer T, Bakkerud F (PhD student), Medeiros A, Werner S, Bronstad E, Rognmo O, Mangner N, Linke A, Schuler G, Silva GJ, Wisloff U, Adams V. Heart failure with preserved ejection fraction induces molecular, mitochondrial, histological, and functional impairments in rat respiratory and limb skeletal muscle. Eur J Heart Failure 17(3): 263-72, 2015

How good is research at University of Leeds in Sport and Exercise Sciences, Leisure and Tourism?

FTE Category A staff submitted: 12.50

Research output data provided by the Research Excellence Framework (REF)

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