Investigating the mechanisms controlling contraction in the first skeletal muscle displaying intrinsic pace maker properties

Even when removed from the body, the human heart will continue to beat (contract). However, in contrast, when a normal muscle is taken out of the body, it will not contract unless externally stimulated in some manner (e.g. electrical stimulation). We have recently found a very special skeletal muscle that goes against this central biological principle. This muscle is called the lymph heart and it beats even though it is not linked to any nerves. We want to carry out research to understand what allows this muscle to contract when it should not really be able to do so. In particular, we want to look at the molecules that allow it to make its own electrical signal and find out how this electrical signal spreads across the muscle to enable contraction and so to function as a pump. We believe that this muscle represents an intermediate form of tissue that shows features of both heart and muscle. At present we know very little about this muscle and investigations into the working of this tissue will be of great interest and use to scientists studying both of these tissues. We believe that a strong basic understanding of this tissue, may enable us and others to engineer muscle into self-contracting tissues like the heart, thereby opening new avenues for developing treatment in heart and muscular diseases.

Contraction of cardiac and smooth muscle is controlled by an intrinsic pace-maker that generates an action potential from within the tissue itself. In contrast, it is generally held that action potential originating in the nervous system is essential for the contraction of skeletal muscle. However our recent studies fundamentally challenge this notion by showing that a specialised skeletal muscle called the lymph heart is able to contract in the absence of any innervation. In this proposal we will ascertain the mechanisms underlying lymph heart contraction without afferent neural input. We will address two major questions to elucidate the mechanisms of this unique phenomenon: (1) Is contraction of the skeletal muscle mediated by a specifically located pace-maker or do all cells of the lymph heart possess an intrinsic ability to contract? (2) Which molecular and electrophysiological mechanisms are responsible for generating, regulating and propagating the action potentials needed for the contraction of the lymph heart in order for it to function as a pump? We have a unique opportunity to answer these questions by establishing a multidisciplinary, multicentre collaboration between Ketan Patel, Ben Whalley and David Becker, thereby bringing together expertise in muscle biology, electrophysiology and live cell imaging.

Beneficiaries The experiments outlined in the proposal address a new cell type and therefore are likely to be useful to cell biologists. In turn these results could be used by the research councils to exploit these findings for longer term investigations especially to develop these findings for therapeutic applications. Communication and Engagement with Wider Public The universities involved in this collaboration are fully engaged with the wider public to advertise the work that goes on in the research facilities in their communities. Engagement is fostered through two major channels: (1) Open access to the research facilities to the general public (group tours, work placements etc). (2) Communication of results at public forums. Both institutes have lecture series that are open to the general public. Secondly, the PIs have all engaged in speaking to the public though television of radio presentations. In addition, each institute has public relations personnel who are employed to communicate research activities and how these are activities relate to the members of the general public. Collaboration and Management This project has a strong collaborative leaning and is essential for the execution of this multi-disciplinary project. We bring together experts in skeletal muscle development, electrophysiology and live cell imaging for the execution of this project. The overall management of the project will lie with Professor Patel who will work closely with Professor Becker and Dr Whalley to ensure that the targets of this projects are met. The collaborators have been in intensive discussion during the development of this project and a strong management programme has been formulated during this time. Exploitation and Application This work involves the investigation of a novel cell type and as such represents research at the early characterisation of a novel feature. We see long term potential exploitation of our findings but a stronger case will develop during the project. However, we have on board a PI who has extensive expertise in taking novel biological concepts into the market place. Professor Becker has secured $20m funding in order to take his technological advances in the field of connexion biology (a major focus of this work).