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

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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?