Will muscle-boosting meds be the next big thing after GLP-1 drugs?

Sustaining muscle in old age can be difficult

James Ross/Millennium Images, UK

Building muscle is hard. Stop working out for just a few days and you start to lose it. What’s more, it gets tougher and tougher just to maintain muscle as we get older. But now a number of muscle-boosting drugs are being tested in clinical trials. Is staying strong into old age about to get much easier?

The origin of this kind of muscle-boosting drug dates back to the 1990s, when a team in the US discovered a protein resembling known growth factors, which boost or hinder cell growth. Mutating the gene to block the protein’s function resulted in mighty mice, in which each muscle was two to three times the usual size.

The researchers went on to show that mutations in what they called myostatin are behind the “double muscling” seen in some breeds of animals, such as Belgian Blue cattle or bully whippet dogs. Then, in 2004, they reported that a 4-year-old boy with unusually large muscles had mutations in the myostatin gene. All this suggested that blocking myostatin in people would dramatically boost muscle size.

Essentially, muscle is costly to maintain in energy terms, so we’ve evolved to use it or lose it. In addition to muscle-boosting growth factors released when we use our muscles, there are muscle-shrinking factors like myostatin. The size of our muscles is determined by the balance between them: shift the dial by blocking myostatin and the same level of exercise should result in larger muscles.

That could make a big difference in older age. “You want people to maintain mobility with old age, be it to get up a flight of stairs, go to the bathroom or go to the store,” says David Glass at Regeneron, one of the companies developing muscle-boosting drugs.

“But starting in your 30s, you lose strength as you get older,” he says. “There are naturally occurring mechanisms that make it harder to get a benefit from [exercise].”

Staying mobile is just one benefit of being more muscular. The fact that maintaining big muscles requires a lot of calories is an advantage in a world where many of us eat too much. Boosting muscles should help prevent or treat obesity as well as related conditions such as diabetes.

“Muscle is really important not only for preventing frailty as we age, but also for metabolic health as well, because it stores the majority of sugar after a meal,” says Brendan Gabriel at the University of Aberdeen in the UK.

There are also many muscle-wasting conditions, such as Duchenne muscular dystrophy, where muscle-boosting drugs should help. But while the first generation of myostatin blockers produced dramatic effects in animals like mice, in people they’ve been a disappointment.

Why? It’s partly because in people there’s another major muscle-shrinking factor called activin A, which binds to the same receptors as myostatin. “You need to block both, whereas in the mouse you get this dramatic response just by blocking myostatin,” says Glass.

Even then, the maximum increase in muscle size in people seems to be around 10 per cent, compared with 50 per cent in mice. The pathway is just less powerful in people, says Glass. “I can’t tell you why. I don’t know.”

Another major issue is unwanted side effects. Myostatin and activin A are both members of a large “superfamily” of protein growth factors with a similar structure. Drugs that bind to myostatin or activin can also bind to other key growth factors, affecting things such as blood clotting.

All this means that drug developers have had to rethink their approach. One option being explored is to block the receptors that myostatin and activin A bind to. Another is to block the precursor form of myostatin, which has a more distinctive structure than that of the active protein. Some companies are exploring other approaches that don’t involve myostatin at all.

There is also concern that the long-term use of myostatin-blocking drugs could affect a vital muscle: the heart. But in a study that came out in March, Glass and his colleagues analysed data on a million people in the UK Biobank study. They found no signs of cardiovascular issues in people with mutations affecting myostatin function – but these people did have up to 10 per cent more muscle and a higher grip strength.

Despite the disappointing initial results, pharmaceutical companies have got a lot more interested in developing muscle-boosting drugs thanks to the runaway success of GLP-1 weight-loss drugs. That’s because it turns out that GLP-1 drugs result in a loss of muscle mass as well as fat.

When people stop taking GLP-1 drugs, they often regain lost fat very quickly, say Gabriel. But they don’t regain the muscle as fast. This has led to concern that muscle loss could become a major problem in people who repeatedly start and stop taking these drugs.

So, many of the newer myostatin-targeting drugs are now being tested in combination with GLP-1 drugs. The hope is that they can not only reduce or prevent muscle loss, but also enhance weight loss, because of the extra energy needed to maintain muscle.

The results of one animal trial, published last year, caused much excitement in some corners of the internet. Regeneron gave obese cynomolgus monkeys a triple therapy consisting of the GLP-1 drug semaglutide, a myostatin precursor-targeting antibody called trevogrumab and an activin A-targeting antibody called garetosmab. The monkeys gained lean mass while losing a lot more weight than animals given semaglutide alone. One YouTuber with a large following suggested these drugs would replace steroids for bodybuilders.

But interim results from Regeneron’s phase II trial in humans are less positive. The triple combo did prevent 80 per cent of the lean mass loss seen with semaglutide alone, while boosting fat loss. But a third of these people developed side effects severe enough for them to stop taking the drugs.

“There are side effects that would make us not want to go forward,” says Glass. Regeneron is now working to understand why the side effects were so severe, he says.

But trevogrumab did halve the loss of lean mass when taken with semaglutide, while boosting fat loss. Similar phase II results were reported in June for another myostatin precursor-targeting antibody called apitegromab.

“Apitegromab is the most promising,” says Gabriel. It is more selective than trevogrumab for the myostatin precursor specific to muscle, he says, so should have fewer side effects.

There are some caveats about these results. Lean mass here refers to everything that isn’t fat or bone, meaning it includes more than just muscle. Nor did these studies show that people who lose less lean mass are stronger than those who don’t. But Glass says there are issues with the way strength is tested.

“The problem with a lot of the strength tests that have been done is that they’re very short-term, motivation-based exercises,” he says. “And if you go to the gym, I’m sure you know that your output on one day is very different than your output on another day.”

However, in a phase III trial for treating spinal muscular atrophy, apitegromab did improve children’s ability to perform various movements. It could be approved in the US for this purpose in September, making it the first-ever myostatin blocker to reach the market – a huge milestone in the field if it happens.

The next big milestone could be the approval of a myostatin blocker for use in combination with GLP-1 drugs, leading to the widespread use of these muscle-boosting medications. If that’s successful, the next step could be rolling out myostatin blockers for older people more generally.

To be clear, bar a major breakthrough, we aren’t about to see 70-year-olds running around with physiques like Arnold Schwarzenegger in his prime anytime soon. “But just maintaining muscle for older people, I think you’d be helping them,” says Glass.

Of course, if they work, a lot of younger people will want these drugs too. Glass sees this as a distraction from the serious issue of dealing with a growing population of older people. “Everyone gravitates to the trivial thing of, ‘Oh, you know, people will use this just to be jacked’,” he says.

But the use of anabolic steroids is common despite the huge list of serious effects, from “roid rage” to heart problems. If some people swap steroids for myostatin blockers, even if they are less effective, it would reduce the harm done. And if myostatin blockers really can safely boost muscle mass, they should have health benefits in younger people, too.