Muscle loss caused by anti-inflammatory drugs may depend on time and sex

Worldwide, millions of people rely on artificial glucocorticoids, also known as cortisones. These medicines, such as prednisone, prednisolone, dexamethasone, and betamethasone, are based on the body’s own cortisol. They help reduce inflammation or suppress the immune system in conditions such as rheumatoid arthritis, Crohn’s disease, lupus, or severe asthma.

However, people who use cortisones long-term often experience side effects. One of these is muscle atrophy: the thinning and weakening of muscles. People with muscle atrophy lose strength, tire more easily, or struggle with movement. Muscle atrophy also occurs in Cushing’s syndrome, a disease in which the body produces too much cortisol.

The biological clock

The biological clock influences the natural cortisol level in the body. In humans, it is usually highest in the morning. This is needed to wake us up and make us active. During the day, cortisol gradually decreases. In the evening and at night, it reaches its lowest point, allowing us to sleep.

Other studies have shown that a disrupted day-night rhythm affects our metabolism. Sheng suspected that this rhythm could also influence the use of glucocorticoids. After all, when our daily rhythm is disturbed, there is often also a disturbance in the natural cortisol rhythm.

Comparing side effects in morning and evening

To test this, he compared the effect of taking the drug betamethasone in the morning versus in the evening. He did this by giving the drug to mice in the laboratory at these two different times. He discovered that the timing of administration influenced how the animals processed sugar (glucose). Administering the drugs in the morning (when the mice are inactive because they are nocturnal) led to insulin resistance, meaning they responded less well to insulin. In the evening (when the animals are active), these side effects were less pronounced.

According to Sheng, these results show that the timing of drug administration can play an important role. The next step is to investigate whether the same effect occurs in humans. “In that case, we might be able to reduce side effects of medications by taking into account the time of intake,” he says.

Sex differences

In the second part of his research, Sheng looked at differences between males and females regarding muscle atrophy caused by long-term cortisone use. To do this, he exposed mice in the lab to corticosterone for a long period—a hormone that is as important for rodents as cortisol is for humans. He observed that female mice experienced a greater loss of muscle function than male mice, even though the loss of muscle mass was the same in both sexes.

In an attempt to explain these differences, Sheng conducted a so-called transcriptome analysis. This technique allowed him to measure which genes were active when mice were exposed to corticosterone. By comparing this with mice that had not received the hormone, he could see what the drug does at the genetic level.

Perhaps treating men and women differently

The analysis showed that male and female mice respond differently at the genetic level to long-term corticosterone exposure. Although both sexes developed muscle atrophy after prolonged use of the hormone, the genetic pathway leading to that point was different. Sheng suspects that sex hormones, such as testosterone, play a decisive role in this. Exactly how that role works remains to be further investigated.

According to the researcher, these findings may be of great importance for treating people with cortisone-induced muscle atrophy. “In the future, it may be possible to treat men and women differently.” Before that can happen, more research is needed into the complex interaction between sex hormones and glucocorticoids, both in the laboratory and in clinical studies with humans.

Sheng Li obtained his PhD on April 23rd at the Faculty of Medicine/LUMC of Leiden University. His supervisors were Prof. Dr. Onno Meijer and Dr. Jan Kroon. You can find the publication of the dissertation here.