ABOVE: Participants in the exercise study

Whether you’re peddling a bike, running on a treadmill, or hiking in the woods, regular aerobic exercise powerfully protects you from cardiovascular and metabolic disease. But the precise molecular mechanisms connecting regular activity to improved health have been unclear. A study published April 14 in Science Advances makes major gains in this understanding. Building off previous work on single bouts of exercise, researchers at Ghent University in Belgium found that when humans perform long-term training, histamine receptors are activated, improving a variety of cardiometabolic risk factors, from insulin sensitivity to aerobic capacity and blood vessel health.

“It’s awesome, it’s a very cool paper,” says University of Oregon exercise physiologist John Halliwill, who was not involved in the study. “This is one of a few studies out there finally looking at these molecular transducers, and this is the only one out there on histamine that showed that it has this lasting impact on how we adapt to exercise. . . . It’s not just a signal associated with allergies and asthma, wound healing. It seems to have a hand in everything related to exercise, which is quite amazing.”

Histamine is typically associated with allergic reactions and gastric acid secretion, but in recent years, Halliwill and others have shown that blocking histamine H1 and H2 receptors reduces people’s muscular blood flow during recovery from a single bout of exercise. Blocking histamine receptors also alters the transcription of about one-quarter of the genes that are differentially expressed post-exercise, Halliwill says. Together, the findings point to histamine as a positive mediator of exercise’s effects.

See “Extreme Exercise Carries Metabolic Consequences

Exercise physiologist Wim Derave of Ghent University in Belgium and his PhD student Thibaux Van der Stede wanted to know whether histamine also played a role in longer-term exercise training, the kind with known health benefits. They enrolled 20 heathy men who didn’t exercise in a program of high intensity interval training (HIIT) three times a week for six weeks. One hour before each exercise session, half the men received drugs that blocked the H1 and H2 histamine receptors, and the other half received a placebo. The histamine blockers were a combination of a common allergy medication, fexofenadine, which blocks the H1 receptor, and either ranitidine, an acid-reducing medicine the US Food and Drug Administration removed from the market last year, or the antacid famotidine, both of which block H2. Doses were higher than those taken to treat allergies or acid reflux.

The result showed that a lot of the beneficial effects of exercise were impaired when we blocked the histamine receptors.

—Thibaux Van der Stede, Ghent University

The team found that, after six weeks of exercise, men whose histamine receptors had been blocked experienced significantly less improvement in several parameters related to exercise performance, as well as a smaller improvement in the ability of mitochondria to produce energy, than did those who received a placebo. When the researchers gave the men glucose tolerance tests before and after the six weeks of training, they found that, in men on placebo, insulin’s ability to move glucose from the bloodstream into cells improved after exercise, but there was no improvement post-exercise in men on histamine blockers. The treated participants also had less capillary formation in their leg muscles, reflecting poorer health of the microvasculature system, and no increase in endothelial nitric oxide synthase, which is key to healthy endothelial cell function, after the six weeks of exercise training compared with men on placebo.

“The result showed that a lot of the beneficial effects of exercise were impaired when we blocked the histamine receptors,” says Van der Stede. “It is really the first time that we see that histamine is involved in any of these processes.”

“This is a really nice piece of basic science in humans,” says physiologist Michael Joyner of the Mayo Clinic who did not participate in the study. “Any time you can find a target that does several things is most interesting, and that these things are part of a suite of adaptations to exercise, both acute and chronic, is very, very interesting.”

Histamine blockers’ interference with exercise adaptation

Understanding the specific molecular effects of exercise training is important for many reasons, but, in particular, it could help optimize training regimens. “It could be helpful if we understand what type of exercise is better in liberating histamine than another, that could help us improve training or improve health with an exercise prescription,” says Derave.

In addition, understanding whether certain drugs or supplements interfere with the benefits of training is important. In this study, although the researchers gave the subjects a combination of commonly used medications to block two of the four histamine receptors, most people don’t take both at the same time, and not at the high levels the team used in the study. Derave also notes that it’s unclear if the same detrimental effects would happen if the study only blocked one of the receptors. “We can’t be completely sure what the relevance is,” says Derave, “but it could be that people who train for sport or health don’t get the full bang for their buck because they simultaneously take drugs. That is an issue and it should be explored in further studies.”

Another future direction will be to confirm these results in women, says Derave. Although he and his colleagues did include women in an initial study of acute exercise, the current study only included men. “We should still confirm this in women,” Derave says. Halliwill agrees. “For too long we have not included enough women in our studies to be able to say definitively that men and women are behaving differently in response to this intervention or these stimuli.”

T. Van der Stede et al., “Histamine H1 and H2 receptors are essential transducers of the integrative exercise training response in humans,” Sci Adv, 7:eabf2856, 2021.