Researchers have modified a drug currently used to treat asthma so that it instead stimulates muscle growth and weight loss. In the longer term, the new principle could have implications for treating people with type 2 diabetes, obesity and age-related loss of muscle mass.
Imagine a drug that could make muscles grow while helping the body handle sugar better. It sounds like two completely different problems – but that is exactly what makes beta-2 agonists special.
Most people know them today from asthma medicine, where they relax the airways and make breathing easier. In contrast to conventional asthma drugs, the new compound is developed as a once-daily oral pill, not an inhaler.
Less well known is that the same drugs can also stimulate muscle growth – so effectively that they are banned as performance-enhancing substances in elite sports.
The challenge is that the body quickly gets used to the signal. Beta-2 receptors become desensitised – they simply stop responding – and the effect disappears after a few days or weeks.
“It’s as if the body gets used to the signal and starts to ignore it,” explains Tore Bengtsson, Professor, Department of Molecular Biosciences, Wenner-Gren Institute, Stockholm University, Sweden.
For decades, this limitation has prevented the broader use of beta-2 agonists. Researchers have now overcome the problem by developing a biased beta-2 agonist, which selectively activates the beneficial signals inside the cell while avoiding those that dampen the effect – thereby maintaining its action week after week and month after month.
Over that time, the drug causes muscles to grow while simultaneously drawing sugar out of the blood – a combination of effects that together strongly promote health.
“We have developed something that could benefit people with obesity, diabetes, muscle disease or age-related loss of muscle mass. It holds great promise in a future in which the pharmaceutical industry increasingly develops medicines that not only treat disease but also improve overall health,” says Tore Bengtsson.
The research has been published in Cell.
A breakthrough that took 12 years
The breakthrough did not come out of the blue. Tore Bengtsson and colleagues have spent 12 years developing a beta-2 agonist with the desired effects – without the familiar drawbacks such as side-effects and rapid loss of efficacy.
The requirements were demanding: the drug candidate had to be suitable for use as a pill and able to maintain its effect over time.
Years of research ultimately led to ATR-258, which appears to meet all these criteria.
In controlled experiments in mice, the researchers showed that the drug candidate normalises blood sugar, reduces fat mass and increases muscle mass.
“ATR-258 is very potent and genuinely impressive in terms of how much it can improve health,” says Tore Bengtsson.
Sorting the body’s signals
Beta-2 agonists can perform so many different functions in the body because of the presence of beta-2 receptors in many different tissues.
That is precisely why the challenge has been to preserve the beneficial effects while avoiding those that cause side-effects or quickly dampen the response.
When a beta-2 agonist binds to a beta-2 receptor, it triggers several signals inside the cell at once: some make muscles grow and draw sugar out of the blood; others act as a brake that gradually weakens the effect; and a third group can cause side-effects.
“It’s a bit like pressing several buttons at once,” explains Tore Bengtsson.
It is exactly this complexity that has made the task so difficult: preserving the beneficial signals while avoiding those that either blunt the effect or cause side-effects.
“ATR-258 is designed to activate the good signals and dampen the harmful ones – like a smart beta-2 agonist that keeps muscles active and improves blood sugar control with far fewer side-effects. Before ATR-258, no one had succeeded in designing a beta-2 agonist that does just that,” says Tore Bengtsson.
From laboratory to clinic
With this breakthrough in place, the research has moved from the laboratory towards clinical reality – a crucial step if a new principle is to reach patients.
“This is where we begin to see whether the idea also works outside the laboratory,” says Tore Bengtsson.
Early clinical trials in humans have already shown that ATR-258 is safe to use. The next studies will now determine whether it works as well for people as it does in mice.
“This is the crucial next step,” says Tore Bengtsson.
Tore Bengtsson sees several areas in which a drug based on ATR-258 could be relevant. One obvious example is treatment with modern weight-loss drugs, which often lead to loss of both fat and muscle mass.
“When we combine ATR-258 with weight-loss drugs based on GLP-1, we see that the mice retain much more muscle mass while the fat continues to disappear,” says Tore Bengtsson.
More muscle – even late in life
It is also clear that ATR-258 could be relevant for people with type 2 diabetes.
It increases muscle mass by stimulating muscles to absorb more sugar and energy from the blood – and as muscle mass increases, blood sugar levels fall, which is particularly beneficial for people with diabetes.
Finally, Tore Bengtsson sees considerable potential in developing ATR-258 as a muscle-preserving drug.
This could benefit both people with muscle disease and older individuals, who naturally lose around 1% of their muscle mass each year.
The less muscle you have, the greater the risk of illness, loss of mobility, dependence on assistance and serious falls.
Muscle mass plays a crucial role in how we cope as we age – not only for our health but also for our ability to remain independent, active and without needing extensive care.
The perspective therefore extends far beyond any single disease – into an area in which ageing populations and modern lifestyles are placing increasing pressure on healthcare systems around the world.
“ATR-258 should not necessarily be developed only for treatment for obesity, type 2 diabetes or reduced muscle strength. Many older people could benefit from more muscle, and if we can help them achieve that with one pill a day, it would lead to a healthier old age with fewer hospital visits. It would be like getting people to exercise without actually moving,” concludes Tore Bengtsson.
