Maintenance of adequate muscle and bone masses requires a minimum rate of physical activity. We have measured muscle wasting at ~15% per month in patients with legs immobilized in full-length plaster casts and muscle wasting in space appears to be faster than this. Physical activity per se is not the only criterion, however, since countermeasures involving dynamic exercise have little value in ameliorating the muscle loss in space. Work in animals shows clearly that immobility leads to bone loss and the relatively sparse data available for human beings suggests that even quite short term immobility also leads to measurable bone thinning; in space, however, the loss of bone (in some sites) is much more dramatic - up to 2% per month.

The relative lack of information about changes in the rates of the processes that determine the changes in muscle and bone mass hampers our understanding. For skeletal muscle it is now quite clear that there are changes both in rates of transcription of genes and in translation of their products, which are markedly affected by physical activity. We have recently shown that concentric and eccentric exercise will cause contraction mode-specific alterations in expression of muscle genes within 3 h of exercise; there are consonant changes in elements of signalling pathways such as p70 s6 kinase, AKT, MAP kinases and p38. No such data is yet available on effects of microgravity in human beings. There are also substantial increases in the rate of muscle protein turnover with resistance exercise, muscle protein synthesis being accelerated markedly with smaller increases in breakdown (in the fed state) leading to accretion of muscle protein. During immobilization, muscle protein synthesis falls with smaller falls in breakdown so that muscle wasting occurs through a supply side failure. Physical activity appears to increase the slope of the dose response relationship between protein synthesis and essential amino acid availability, i.e. increase the sensitivity of muscle to feeding. No information is currently available about the relationship between immobilization and the sensitivity of protein synthesis but extrapolating, it would be predicted that immobilization leads to a decrease in sensitivity. It is also a possibility that the normal inhibition of breakdown by food is also sensitised by physical activity so that under conditions of immobilization this inhibiting process would be blunted. Rates of synthesis of classes of proteins and even individual proteins of sufficient abundance (e.g. myosin heavy chain, cytochome C-oxidase, aldolase, creatine kinase) can be measured with great sensitivity and precision using stable isotope techniques with muscle samples obtained by biopsy. Although it is unlikely that biopsy techniques could be applied in space, it would certainly be possible to obtain a good estimate of the rates of muscle protein synthesis by administering isotopes in space and conducting the biopsies on earth.

In the case of bone, our understanding of the control of turnover of the major bone protein, i.e. collagen, is much less well advanced. Very few studies have been carried out investigating the turnover of bone collagen in vivo in animals and until our group developed appropriate methods, no information whatsoever was available on the rates of human bone collagen turnover. We have now developed techniques using both stable isotope labelled (15N or 13C) proline (by infusion) and 18O2 (as a respiratory gas), both of which become incorporated into collagen as labelled hydroxyproline. We now have values for normal children, for children who have suffered burns of >40% BSA, for young healthy men and for patients undergoing hip replacement. We have been able to demonstrate marked differences in the rates of turnover of different fractions of bone collagen with developmental decreases in turnover, decreases in bone collagen synthesis in traumatized children (possibly via shut down of IGF-1 production) and somewhat surprisingly, increased bone collagen synthesis in elderly patients with osteoarthritis. The development of the 18O2 method should enable bone collagen synthesis to be measured in space simply by exposing astronauts to low concentrations of 18O2 in the ambient air and determining the incorporation of 18O into collagen in a single bone biopsy taken after flight. Bone collagen breakdown could be determined by measuring the difference between collagen labelling achieved on earth pre flight and the loss of non-recyclable label from 18O hydroxyproline in bone collagen during space flight.
These techniques should, for the first time, enable us to obtain specific measurements of the turnover of the collagen matrix of bone both on earth and in space.

Why should we be interested in immobility and microgravity on muscle and bone? First unless we discover ways of countering muscle and bone loss in astronauts, the only possibility of travelling to Mars will be in a space vehicle that produces its own gravity. Furthermore, the very rapid wasting of muscle and bone which occurs in space appears to reflect an increase in the catabolic signals involved which may be better picked up by studies of astronauts. Thirdly, the question of muscle and bone wasting is of great general significance to an ageing population in which frailty and ways of countering it will be increasingly important problems and work on models of microgravity on earth (e.g. head down bed rest, plaster casting, single leg unweighting) will be relevant in attempting to counter frailty in the elderly and sick. Fourthly, the challenge of working in space and the technical constraints thereof, may allow us to fine tune and improve techniques (e.g. for frequent measurement by 13C breath tests of gastric emptying and gut motility- major problems in space) with the production of new techniques and instrumentation which may be then fully applied on earth. A good example of this would be the production of an on-line 13CO2 analyser with a sufficiently small footprint to be used in the Shuttle or in the International Space Station that could then be used in GPs surgeries by practice nurses.

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