BEDREST Determination of the time-course of the development of insulin resistance, and associated molecular and muscular adaptations during prolonged

This project will provide the foundation for future translational research to combat inactivity. Reduced physical activity impacts heavily on quality of life, and increases both morbidity and mortality. The current World Health Organisation (WHO) recommendation for physical activity is set at a minimum of 150 minutes of moderate intensity aerobic activity per week in individuals aged 18-64, or at least 75 minutes of vigorous intensity aerobic physical activity. However, it has been estimated by WHO that in 2009 17% of adults worldwide failed to meet this guideline, and by 2012 this figure had increased to 31%, pointing to a worsening world-wide public health problem. This point is startlingly illustrated by the WHO estimation that physical inactivity is now the fourth leading cause of death worldwide, accounting for 6% of deaths globally. Furthermore, the association between physical inactivity and morbidity is illustrated by evidence suggesting that physical inactivity is causative in the development of many modern metabolic diseases including obesity, insulin resistance, type 2 diabetes, dyslipidemia and hypertension, amongst others; with physical inactivity being cited by WHO as the principle cause of 27% of diabetes and 30% of ischaemic heart disease cases. In addition to the reductions in daily physical activity brought about by a sedentary lifestyle, prolonged periods of physical inactivity occur as a consequence of injury, disease, disabilities and advanced age. Taken together, the increased prevalence of health disorders related to inactivity exerts a substantial economic burden, not only in medical care costs but also the cost of improving quality of life. Skeletal muscle Insulin resistance can be defined as the inability of our muscles to respond to the hormone insulin to lower blood glucose levels, and is also major risk factor for the development of type 2 diabetes, cardiovascular disease, musculoskeletal disorders and some cancers. We know that the inactivity-associated loss of muscle mass and muscle fat accumulation is a major cause of insulin resistance, but we do not know the time course or mechanistic basis of these events. Furthermore, we do not know whether the accelerated loss of muscle mass that occurs beyond 45 years of age represents an added burden to maintaining insulin sensitivity than that from inactivity per se, and if it does, what magnitude of metabolic insult this represents. Thus, a clear understanding of the extent and temporal relationships of physiological adaptation to physical inactivity is therefore vital in the development of effective countermeasures that are at present missing. In this regard, bed-rest models enable valuable insight to be obtained regarding the physiological impact of short and long-term physical inactivity on human insulin resistance, and so the aim of the present proposal is to utilise a 60-day bed-rest human study design to elucidate the following:

(i) What is the rate of onset of leg and whole body insulin resistance during bed rest?
(ii) Does it worsen over time? Seven day bed rest studies suggest not, but temporal data are missing (and particularly leg vs whole body)
(iii) What are the physiological and molecular drivers of immobilization induced muscle insulin resistance, and the relative change in the contribution of each over time?
(iv) What are the temporal changes in muscle gene expression over the course of 60 days bed rest linked to atrophy, fuel metabolism, and is there commonality with genes known to change during space flight in worms?
(v) How does an intervention cocktail containing a number of ingredients that can modulate muscle insulin resistance, carbohydrate oxidation and mitochondrial function affect these measurement parameters?
(vi) What is the rate of restoration of leg and whole body insulin sensitivity and the associated physiological and molecular changes post bed-rest, and how is this modulated by muscular contraction?

There are currently significant gaps in our understanding of the rate and magnitude of physiological dysregulation that occurs during bed rest (as most studies to date have considered mainly pre and post-bed rest time-points), and the sites and mechanisms controlling bed rest induced dysregulation. Thus, there is an urgent need for detailed time-course studies. This insight is urgently needed because it may be that interventions aimed at minimizing bed-rest induced physiological dysregulation could be most effectively focused on time periods when the rate of onset of physiological dysregulation is likely to be at its greatest. For example, we are of the opinion that bed rest induced muscle insulin resistance develops almost entirely over the initial few days of bed rest and then stabilizes at a new steady-state. Importantly, focused intervention could therefore reduce the magnitude development of physiological dysregulation, and also presumably reduce time commitment needed to perform countermeasures over a chronic period of bed rest. Thus, we propose to test our objectives on experimental visits before and following 1, 14, and 55 days of bed rest, and again after 2 and 14 days of rehabilitation, using the glucose clamp and leg arterio-venous balance techniques combined with muscle biopsy sampling to directly measure whole body and muscle insulin sensitivity and associated physiological and molecular changes. Furthermore, we will determine whether a nutritional intervention that has been shown to influence metabolism in rodent immobilisation models, is able to prevent the development of insulin resistance in humans. Importantly, we will utilise a novel targeted molecular approach by identifying temporal changes in muscle gene expression over the course of 60 days bed rest, including transcripts known to change in prolonged space flight in the C. elegans worm. We are confident our approach will elucidate specific drivers of bed-rest induced insulin resistance.

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 three ways. First, the appointed researchers will gain experience with prolonged bed-rest studies which are not commonly conducted in the UK. Second, the appointed researchers will gain experience with truly collaborative European research. Third, the investigators will remain and/or gain knowledge of the international politics associated with spaceflight research. All of these types of professional development will aid in their ability to seek further employment, with the management experiences being the most transferable skill they will continue to develop. These impacts will be felt within the first year and fully realized in three to five 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. 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 within two-five years as we present and publish our findings. Additionally, the UK space industry will benefit by having an actively engaged space life sciences researcher sitting on the UK space agency advisory board 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 within the first year 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 Aging, Cancer Research UK, The Muscular Dystrophy Campaign). Lastly, the 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.