by Caroline Williams
New Scientist: SO YOU joined a gym, stuck to your training schedule and, even if you say so yourself, you look good and feel great. In just a few months you have gone from weedy geek to muscular athlete, with biceps bigger than Madonna’s. But there is a catch, of course. To stay looking this good you’ll have to keep lifting those weights.
Before you slump on the couch in despair, help could be at hand. Researchers studying how muscles build up and break down believe they are close to creating a drug to stop the body dismantling muscle when we stop using it. Their aim is to tackle weakness in the sick and elderly, and to help make long space flights feasible for humans. However, such a drug should also make staying in shape that bit easier – a boon for couch potatoes and, of course, would-be sports cheats.
Having our muscles beef up when we use them and wither away when we don’t is the body’s way of making the best possible use of resources. Do some muscle-challenging exercise and your muscle cells expand to take the strain. Rest up and the muscle proteins will start breaking down almost as soon as you stop moving. Idle muscle is an unnecessary metabolic expense.
For most of us, muscle growth and breakdown exist in a subtle balance, and unless our diet or exercise regime changes dramatically we hardly notice it. But if injury to the bones, muscles or their nerve supply puts part of the body out of action, or the body becomes starved of food, the balance shifts and muscle breakdown outweighs synthesis.
For people confined to bed for long periods of time, or for astronauts in microgravity, muscle wasting is a serious problem. Wasting, or atrophy, is a symptom not only of disuse and injury, but of many diseases, including kidney failure, cancer and AIDS. Once enough muscle has been lost a vicious cycle sets in as exercise becomes increasingly difficult, which in turn leads to disuse and further atrophy.
Despite more than three decades of research into alternatives, the only way to stop such patients losing muscle is a long course of physiotherapy involving weight-bearing exercise, but this is of little use to the weakest and sickest – and in most cases starts only after wasting has already set in.
The use of anabolic steroids is being explored for some conditions. But these compounds have a huge range of effects on the body besides promoting muscle growth, some of them undesirable, and only appear to work well in conjunction with exercise. A specific treatment for prevent wasting until patients are well enough to get back on their feet, or until astronauts have arrived at their destination, would be ideal.
Alfred Goldberg, a cell biologist at Harvard University, began studying muscle atrophy in the late 1960s. At the time, virtually nothing was known about what prompts muscles to grow and shrink, but a series of discoveries in the 1980s and 90s changed all that.
What he and others discovered was that, rather than being a passive side effect of disuse or disease, muscle wasting is an active process controlled by a complex genetic pathway. So, if someone found out how it was turned on, it ought to be possible to turn it off.
“Back then we didn’t know the pathway for muscle breakdown,” says Goldberg. “but about five years ago our work showed that no matter what the trigger – disuse, metabolic disease or fasting – the same biochemical programme is responsible.”
The process involves the ubiquitin-proteasome pathway (UPP), the disposal machinery used to break down unwanted proteins in the cell (New Scientist, 17 December 2005, p 36). Once the system has been activated, ubiquitin “destroy me” labels are added to muscle proteins. Tagged proteins are then fed into the proteasome, a barrel-shaped multi-protein complex that chops proteins down into their component amino acids for reuse. This breaks down the muscle filaments within cells, but does not change the number of muscle cells. Instead they become thinner and weaker. Further studies showed that at least 90 genes are involved in atrophy; Goldberg calls them “atrogenes”.
Although it is still unknown which of these genes trigger atrophy, it soon became clear that two of them are essential to the process. Atrogin1 and muRF1, were first described in 2001 and are the only two atrogenes active only during muscle atrophy. They code for ubiquitin ligases, the enzymes that attach the “destroy me” labels to proteins. The genes are barely active in normal muscle but expression levels shoot up in sick animals. Knock out either and muscle wasting all but stops.
“Anti-wasting drugs will inevitably be tempting for athletes”
At around the same time this was discovered, another group led by David Glass at US pharmaceutical company Regeneron found the same two genes (and confusingly named the atrogin1 gene MAFbx). When Glass knocked out each of the two atrogenes in rats, he found they suffered less atrophy after both disuse and disease.
Since then more atrogenes have been found every year. In May this year, a group from Purdue University in West Lafayette, Indiana, reported that they too had found a switch for muscle atrophy. What’s more, an existing drug could turn the switch off.
Gym in a bottle
The Purdue team, led by Amber Pond and Kevin Hannon, found that in mice when muscle atrophy sets in there is increased activity of the gene erg1. This codes for a potassium channel protein found in both skeletal and cardiac muscle tissue. In heart muscle, the channel consists of two variants of the protein, erg1a and erg1b, which help the heart keep its rhythm by letting the muscle repolarise after each beat. A mutation in the erg1 gene causes “long QT” syndrome, in which the heart muscle cannot repolarise fast enough, and which can lead to sudden death.
The Purdue team showed that the erg1a variant stimulates atrophy in skeletal muscle. In muscles that were wasting due to disuse or cancer, they found high levels of expression of erg1a. And when they increased the number of erg1a potassium channels on the surface of muscle cells in mice by adding an extra gene coding for this protein, atrophy set in. Adding a gene for the erg1b version of the protein did not trigger atrophy.
Importantly, the team knew that an existing drug, an antihistamine called astemizole, blocks erg1a channels. When they gave it to mice, it almost completely prevented atrophy in muscles not being used. Animals going about their normal activities even built more muscle.
The team thinks the erg1a protein stimulates the ubiquitin-proteasome pathway, although it is not yet clear exactly how. However, there is a problem. Astemizole not only blocks erg1 channels in skeletal muscle, it also blocks them in the heart, potentially causing long QT syndrome. Because of the risk, astemizole was withdrawn in 1999. If this approach is going to succeed, the researchers will have to find a way to target erg1a in skeletal muscle without blocking erg1 channels in the heart, which consist of both erg1a and erg1b subunits.
Pond believes this should be possible, because erg1a and erg1b differ slightly at one end of the protein chain. “We want to find out what the difference is. Can we target that?” Besides conventional drugs, the team is also investigating the possibility of blocking erg1a expression using a gene-silencing technique known as RNA interference.
Meanwhile Goldberg and the Regeneron team, still working independently, have taken a different approach, focusing on the proteins called transcription factors that turn other genes on or off. In 2004, Goldberg’s team identified one called Foxo that controls the activity of many atrogenes. Disabling Foxo blocks atrophy, and all the evidence so far suggests it could be a good target for future therapies.
For now, there’s still a lot to learn. For instance, insulin and the related hormone insulin-like growth factor 1 (IGF-1), long known to be involved in muscle synthesis, also seem to prevent muscle breakdown by suppressing Foxo and turning off the atrogin1 gene. Boosting levels of IGF1, particularly some recently discovered variants of the protein, greatly increases the strength of mice, even if they don’t exercise. This is why both IGF-1 and insulin are banned in sports. But beyond that, very little is clear. “You don’t see active Foxo in normal muscle because insulin and IGF-1 suppress it,” says Goldberg, “but exactly how inactivity or disease activates Foxo we’re still trying to find out.”
Pond thinks that Foxo could be involved in erg1a-mediated atrophy. The erg1a protein is known to bind to transcription factors like Foxo, so increased erg1a activity might trigger atrophy through interaction with Foxo. “That’s what we’re pursuing now,” she says. Meanwhile, several companies are looking for drugs that block the atrogin1 protein, and Goldberg’s team is looking into whether proteasome inhibitors such as Velcade, used to treat cancer, might slow muscle breakdown.
Pharmaceutical company Wyeth of Madison, New Jersey, has taken seemingly the opposite approach. The company recently began trials in people with muscular dystrophy of an antibody therapy designed to stimulate muscle growth, rather than prevent atrophy (see “Pump up the volume”). While coaxing the body to produce more muscle tissue is different to attempting to turn off wasting, the end result could be the same, and the two pathways are likely to turn out to be linked.
There are still many gaps to be filled in, but those in the field agree that the question is no longer if we can develop anti-wasting treatments, but when. As researchers close in on this target, excitement is mounting about exactly what such treatments could achieve. Patients due to be confined to bed for more than a few days could be given the drug as soon as they begin bed rest to prevent muscle loss that would otherwise slow their recovery. Weaning patients off respirators would become easier as doctors could prevent wasting of the diaphragm. Disease need no longer lead to weakness, and broken bones would not mean long and painful physiotherapy sessions to rebuild muscle strength. And since loss of muscle mass is a major reason why we grow frail with age, an anti-wasting drug could keep older people on their feet and living independently for longer.
The prospect of preventing atrophy is also of great interest to NASA, particularly in view of its much talked-about mission to Mars. By the time astronauts reach the Red Planet they can expect to lose up to 25 per cent of their muscle mass and be too weak to walk, let alone put on a space suit and carry out repairs. That is why Goldberg’s work is funded by the National Space Biomedical Research Institute in Houston, Texas, set up by NASA.
While there are valid medical and space applications for anti-wasting drugs, as a safer alternative to steroids they will inevitably be hugely tempting for athletes too, not to mention the lazy well. Although Goldberg is keen to point out that helping cheats and couch potatoes is not the focus of his work, he admits that it will undoubtedly happen sooner or later.
Of course, muscle size is not everything. Endurance training produces all sorts of other physiological changes, including better blood supply to muscles and more energy-supplying mitochondria in muscle cells. Drugs that maintain muscle size will help keep people strong, but will not keep them fit or provide any of the innumerable other benefits of exercise, from stronger bones to smarter brains.
On the other hand, simply maintaining more muscle will help use up a few extra calories. And being able to stay strong even if you skip gym for a few weeks might encourage people to exercise more rather than less, by making it less painful to get started again.
In the meantime, as we await the arrival of the “gym in a bottle”, you will be pleased to hear that there are two tried and tested ways to lower Foxo levels and prevent muscle atrophy. One is to increase your IGF-1 and the other is to stimulate insulin production. Sound complicated? Not at all. All you’ve got to do is eat regularly and do a bit of exercise. For the moment at least, there’s still no substitute for pumping iron.