Establishing molecular mechanisms of and countermeasures to muscle decline in space

People must ultimately colonize other planetary bodies in order to avoid extinction. This is a long term goal of the world's space agencies. A major biological hurdle to this long term goal is the decay of muscle during spaceflight. Similarly, the decay of muscle with age is a major public health problem in the UK. We have developed a small worm into a model for understanding and countering the effects of spaceflight and age upon muscle. In space, much like human muscle, the muscles of this worm display decreased expression of muscle proteins as the result of decreased expression of a master regulator of muscle gene expression. These worms, like astronauts, also display hints of altered metabolism as the result of altered insulin effects. Here we propose to test if, as predicted from past spaceflight and ground based experiments, these worms are weaker in space. The testing of muscle strength in space has already been reviewed and approved to be flown by NASA. We also propose to test if altered muscle attachments and/or altered insulin signalling cause the changes in worm muscle in flight and if we can reverse these effects by altering muscle attachments or insulin signalling in space. The testing of causes of and counter measures to muscle decline in space has already been reviewed and approved to be flown by ESA. BBSRC funding for these studies will allow us to carry them out and will enhance our understanding of the molecular causes of, consequences of, and countermeasures to muscle decline in space. Based upon the scores this work received by both NASA and ESA, completion of this work will firmly keep the UK at the forefront of the field of space biology. Additionally, as muscle decline with age is a problem for the UK and elsewhere there is the clear possibility that findings from this work may be relevant to understanding and counting the decline of muscle with age on Earth.

We have established the worm C. elegans as a model for studying spaceflight and age induced muscle alteration. Like man, worms display decreased myosin and myoD expression in flight as well as altered expression of genes predicted to be controlled by FOXO. We have shown, on Earth, that RNAi against or mutation in some genes encoding adhesome components, that decline in expression in space, result in weaker worms. We have proposed to NASA to determine if worm strength declines in flight and to ESA to determine if insulin and/or adhesome alteration controls altered gene and protein expression in flight; both proposals have been successful and deemed technically feasible with existing spaceflight hardware. Here we ask for funding to support this selected work. We will use our force measurement device in flight to determine if strength declines as predicted; ground controls and a positive control are included. We will use our past gene expression (affymetrix) and protein expression (iTRAQ) methods to analyse gene and protein expression in wild-type, insulin receptor over expressing, FOXO null, altered adhesome mutant, and in wild-type worms treated with a drug predicted to alter adhesome remodelling. Results from these experiments will tell us if past gene and protein expression changes are indeed relevant to altered muscle physiology in flight and also if gene and protein expression changes are due to altered insulin and/or adhesome function in flight. These results will provide clear direction for the international community on the cause of muscle decline in flight and suggest molecularly based strategies for countering this decline. Additionally, as both muscle attachment proteins and insulin signalling decline in ageing humans it is possible that our results may also be relevant to understanding and treating sarcopenia.

In addition to the academic beneficiaries we believe this work will benefit the staff working on the project, the wider public, the commercial private sector, international government space agencies, charities, and possibly museums. The staff working on this project will benefit in five ways. First, the named researcher will gain experience with laboratory techniques not previously employed by them. Second, the researcher will gain experience running a project. Third, the researcher will gain first-hand experience interacting with the media. Fourth, the researcher will gain knowledge of the international politics associated with spaceflight research; Co-I Etheridge will also increase his abilities in this area. Fifth, all staff working on the project will gain additional experience with classroom and web-based public interaction. All of these types of professional development will aid in ability to seek further employment, with the management experience being the most transferable skill the PDRA will continue to develop. These impacts will be felt within the first year and fully realized in four years. The wider public will benefit from this work in the form of new diagnostics, treatments, and ultimately decreased public healthcare expenditure. The new molecular mechanisms which we identify as regulating muscle can immediately be researched by ourselves or others as potential new diagnostics or therapeutic targets. Successful therapeutics should reduce the public healthcare expenditure on conditions associated with muscle which has lost homeostasis (for example in the aged). Additionally all sectors of the UK will also benefit from increased productivity as the result of decreased loss of work days due to muscle problems. As this is basic research, these impacts will most likely not be felt for at least 10-15 years. Note that we will also capitalize upon the public's interest in spaceflight by specifically engaging school aged children directly in our spaceflight work (see pathways to impact). The commercial private sector will benefit in much the same way that the academic beneficiaries will, specifically by having new targets for the development of diagnostics and therapeutics. These impacts will be felt toward the end of the project as we present and publish our findings. Additionally, the UK space industry will benefit by having an actively engaged space life sciences researcher available to provide advice to the UK Space Agency thereby maximizing economic return to the UK space industry. International government space agencies will also benefit much the same as the academics and commercial sector as they too will have novel targets for diagnostics and therapeutics for the muscle loss seen in astronauts, cosmonauts, and taikonauts. These impacts will be felt toward the end of the project as we present and publish our findings. Charities will also benefit in much the same way, particularly those charities that support increased quality of life in individuals with problems that involve loss of muscle homeostasis (for example: Research into Ageing, Cancer Research UK, The Muscular Dystrophy Campaign). Lastly, the Science Museum, National Space Centre and related museums will benefit from this work by having direct access to individuals, within the UK, who are actively engaged in life sciences research in space (e.g. we can assist them with activities, provide useful international contacts, and/or directly present to visitors). These impacts will be immediate. We will also engage ESA, the UK Space Agency, and museums to explore if it is possibly to display a mock up of the Columbus Science module or other portions of the ISS in the UK.