Energetic and redox homeostasis in hypoxic heart and muscle

The aim of our research is to better understand the cellular mechanisms that underlie abnormalities in energy metabolism that occur in heart and skeletal muscle in metabolic disease states such as heart failure and diabetes. More specifically, this project concerns the roles that tissue hypoxia, and consequent oxidative stress, might play in the transcriptional control of energetics.

Heart failure is characterized by systemically high plasma free fatty acids, systemic and local hypoxia and oxidative stress. The exact role of each of these stresses in the progression of heart failure, and the development of mitochondrial dysfunction in heart and skeletal muscle is not yet clearly established. In models of heart failure it is difficult to tease apart the effects of hypoxia from those of an altered metabolic milieu and it is impossible, therefore, to establish cause and effect, in the context of failure, or to identify what constitutes an adaptation or maladaption.

Mitochondria are the end-consumers of oxygen in the body, and likely modulate the metabolic adaptation to cellular hypoxia by decreasing oxygen dependency at the electron transport chain. This adaptation could involve metabolic switches towards the use of more oxygen-efficient substrates (e.g. glucose instead of fatty acids), improved coupling of the processes of oxidation and phosphorylation at the inner membrane or redistribution of mitochondrial populations within the cell to minimize oxygen concentration gradients. Such changes may be brought about via alterations in the transcription of genes controlled by the hypoxia-inducible factor (HIF) transcription factors.

This project will use chamber-induced hypoxia in whole animals and muscle samples from humans acclimatising to high altitude as part of the second Xtreme Everest expeditions (www.xtreme-everest.co.uk) to investigate mechanisms of adaptation. Techniques will include isolated, working heart perfusions, mitochondrial respiration, western blotting and RT-PCR. Students with experience of these techniques are particularly encouraged to apply.