Is the skeletal muscle the “fountain of cardiac youth”?

Description

The heart is a non-regenerative organ, meaning that any myocardial damage is a permanent feature of the myocardium from that point on. Any treatment for a heart attack tries to reduce the damage to the heart, but our hearts are able protect themselves from ischaemic damage. Our big problem is that we don’t know how to switch it on in man.

Evidence suggests that this cardioprotection can be switched on by causing ischaemia elsewhere in the body, for example, in the arm. We hypothesise that there is something release from the skeletal muscle in the arm that feeds back to protect the heart. In experimental conditions, we can make an arm briefly ischaemic to induce the muscle to release the protective factor into the blood, we can then collect that blood and test the level of protection that we can impart in hypertrophy models in cells.

In this study, remoted conditioned serum from human volunteers will be used to assess the anti-hypertrophic properties in rat cardiomyocytes. We have established models of hypertrophy using angiotensin II, endothelin I and Phenylephrine along with a model of continuous stretch that can induce hypertrophy in isolated cells. In all cases, the remote conditioned serum can prevent this hypertrophy. Using pharmacological modulators of known protective pathways, we will assess the mechanisms by which this anti-hypertrophic effect is occurring. For example, we believe that the humoral factor responsible may involve an opioid-type compound, and so we will use selective receptor blockers to assess the contribution of opioid receptors to this anti-hypertrophic effect.

We will also assess the origin of this protective effect. We believe that that the protective factor is encased within extracellular vesicles. We also have evidence that the vesicles from male and female volunteers, and in young and old might be different.  In this study, the student will use imaging of freshly isolated cardiac cells to assess changes in hypertrophy with different induction protocols, metabolic assessment of control vs hypertrophied cells using seahorse respirometry and the effects that remote conditioned serum has on the metabolic profile of control and hypertrophied cells, together with pharmacological profiling of the hypertrophic response to establish how the serum is protecting against hypertrophy. Finally, using Mass Spec, NMR or Elisa methods, the student will assess the serum for compounds that are identified as potentially having an anti-hypertrophic effect on the cardiac tissue.

The development of heart failure is thought to involve the activation of a number of complex signalling pathways, including Akt and ERK triggered by matrix metalloproteinases. Further evidence suggests that Wnt signalling may have a role in promoting inflammation and fibrosis in heart failure, with further studies suggesting a role for hyperglycaemia-linked PKCβ signalling. Using a human iPSC-cardiomyocyte model, the effects of hypertrophic stimuli on these pathways, and the effectiveness of the cardioprotective perfusate or serum, will be assessed.

This project will be the first to investigate the anti-hypertrophic effects of remote ischaemic conditioning and will work towards identifying factor(s) released by muscles during an ischaemic conditioning responses to have these protective effects. The student will also investigate whether direct modulation of signalling pathways, inhibition or activation of MMP’s, or inhibition of PKCβ may have an anti-hypertrophic effect.

Student experience

The successful student will gain full training in a multitude of techniques, ranging from cell culture, electrophysiology measurements, NMR Metabolomics, fluorescence imaging, metabolic analysis using Seahorse analyser technology, and essential research skills including western blotting, qPCR, immunofluorescence, and ELISA. All techniques are established in the laboratory groups of the supervisory team.

Applicant Information

All postgraduate students undertake the Post Graduate Researcher (PGR) Development Programme which aims to enhance their skills for a successful research experience and career. They are required to maintain an online record of their progress and record their personal and professional development throughout their research degree. The Liverpool Centre for Cardiovascular Science holds monthly research group meetings where students are given opportunities to present their research and meet and interact with their peers and senior researchers. Students are also encouraged to attend the seminar series to gain a breadth of knowledge from related research within the Department of Cardiovascular and Metabolic Medicine and wider research themes across our Institute.

The Institute of Life Course and Medical Science is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a Gold SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives. 

Application is via CV and cover letter to the Project Supervisor email richard.rainbow@liverpool.ac.uk