Newton's force as countermeasure for disuse atrophy.

THE OBSERVATION THAT DISUSE leads to muscle atrophy is an old one, but we still lack a good mechanistic description of what is going on to cause wasting in conditions as diverse as bed rest and spaceflight. In fact, much of the current descriptions of the superficial mechanisms of atrophy come from work funded by space agencies, primarily National Aeronautics and Space Administration but also the European Space Agency. Less glamorously, but quantitatively more important in terms of muscle lost, is the clinical interest that centers around disuse atrophy in hospitalized patients and the physically inactive elderly. Both for astronauts and for patients who are confined to bed, a major question is “how can we stop the wasting?” The obvious answer may seem glib, but “removal of the proximal cause” is easier said than done in many situations, such as with paralyzed patients in intensive care or, indeed, in space. Many of the potential countermeasures applied in space (mainly involving exercise of one sort or another) have turned out to be not useful with little beneficial effect on an astronaut’s muscle. Symons et al. (9) have, however, managed to do the obvious experiment: replacement of the gravitational forces that are normally diminished during bed rest. In their report, the Galveston team applied techniques that have become routine for them. They subjected two groups of healthy young men to 6% head-down tilt during bed rest for 21 days, a technique known to cause substantial wasting of the quadriceps muscle. One group spent the entire period immobile except for about 5 min per day for bowel movements, but the other received what was in effect gravitational therapy: exposure to 1 h per day of longitudinal loading amounting to a force of 2.5 G at the feet. The apparatus to achieve this was a human centrifuge that spun the subjects at 30 rpm (described in Ref. 11). The investigators applied well-validated stable isotope-labeled amino acid tracer techniques to measure muscle protein turnover yielding measures of both the rate of production of protein [muscle protein synthesis (MPS)] and the rate of its removal by proteolysis [muscle protein breakdown (MPB)]. As expected from previous work, bed rest alone caused a depression of MPS of about one-half in the control group, but this was completely abolished in the treatment group. This is an important result for two reasons: first, because it is a confirmation of the simple idea that replacing gravity works! Second, it shows that a relatively small stimulus (2.5 G for 1 h per day) is enough to maintain MPS. There are, however, other interesting aspects to the work that are important. As predicted some 20 years ago (3) and confirmed not only by this work but by the earlier work of Ferrando (5), MPB was not to be elevated by disuse and was unaffected by gravitational therapy. In companion articles, Caiozzo et al. (1) show that the same subjects from the study by Symons et al. (9) show the now predictable (2, 4) only minor rise in genes coding for the ubiquitin ligases atrogin and MuRF1, commonly assumed to be involved in muscle proteolysis. Hence, it is not surprising that MPB is not elevated. Thus the major process driving muscle atrophy in immobilization or bed rest (in healthy young subjects) is depressed MPS, not elevated MPB. This is in marked contrast to much of the literature concerning disuse atrophy in rodents (7, 8, 10) in which elevated MPB appears to be of equal importance to depressed MPS. We still do not know the underlying mechanisms driving down MPS, although the obvious candidates, such as depression of activation by phosphorylation of anabolic signaling molecules, appear not to be important (4, 6). It seems likely that suppression of activation of focal adhesion kinase (FAK) may be an important proximal event (4, 6), but the links between this and regulation of MPS both at the nuclear level and at the ribosome are currently opaque. What is the wider significance of the work? For a start, it means that Convertino’s (3) suggestions of inducing artificial gravity as a sine qua non for long-term spaceflight are bolstered. This may make building and launching a Mars-bound vessel much more expensive, but the alternative is the crippling of astronauts returning from a 3-year voyage to Mars and back. Another important message is that the pharmaceutical industry might wish to stop pursuit of inhibitors of MPB, which are apparently irrelevant in disuse atrophy, and concentrate on looking for ways of boosting MPS. Of course as a well-known phrase has it, “the proof of the pudding is in the eating,” and although Symon’s work shows what is probably the best Earth-based results so far, the technique still has to be shown to work in space. Expensive pudding!