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Cellular mechanisms of detrimental skeletal muscle remodeling induced by cardiac dysfunction


Project Description

The loss of skeletal muscle mass and strength is a key impairment in many disease states. This occurs in both limb and respiratory muscles and leads to pulmonary complications and severe disability. The cellular mechanisms linking primary ‘organ’ dysfunction to secondary loss of muscle mass (i.e. atrophy) and strength (i.e. contractile dysfunction) remain poorly understood, with limited therapeutic treatments available. We recently demonstrated that cardiac dysfunction is a key trigger that can increase muscle weakness, which can be induced by elevated reactive oxygen species and upregulation of E3 ligases linked to the atrophy process. Exercise training, however, has been able to prevent such muscle impairments, and more recently novel small-molecule therapeutics proved effective. Despite this, we still poorly understand: 1) the intracellular signaling pathways inducing muscle weakness; and 2) how exercise-induced functional improvements are translated from the molecular level (and if these can be targeted by small-molecule drugs). This project will use a multidisciplinary approach (in vivo imaging and exercise training, in vitro muscle function, confocal calcium imaging, protein expression, immunohistochemistry, genetic deletion) to answer these questions by using relevant animal disease models to investigate cardiac-induced muscle weakness, with the aim of translating these findings to patients to confirm clinical relevance.

The Faculty of Biological Science is Number 1 in the UK for ‘world-leading’ research in the area of sport and exercise sciences (REF, 2014) and is ranked 3rd in the UK for SES (The Times/Sunday Times Good University Guide 2018; The Guardian University Guide 2018). This is an exciting opportunity to undertake a PhD in this area whilst also contributing to the outstanding teaching on our undergraduate courses. Research in our department incorporates both multi- and inter-disciplinary investigations aimed at improving the understanding of the relationship between physical activity, exercise, health and the predisposition to chronic diseases. Our research uses a contemporary systems-integrative perspective to investigate exercise responses, control mechanisms and exercise adherence. Application and translation spans elite athletes, the elderly, and children as well as patients with chronic heart and lung disease, spinal cord injuries, and motor impairments.

We are seeking PhD applicants with the necessary skills and proven enthusiasm to undertake demonstrating with our Sports and Exercise Sciences undergraduate cohorts. The successful candidate will be expected to undertake 120-250 hours of teaching per year alongside their PhD research. You should hold (or be in the final year of) a strong degree, equivalent to at least a UK upper second class honours, in a relevant discipline and should also have an interest in teaching.

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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