W.Regardless of whether you ride a bike, run on a treadmill or hike in the forest, regular aerobic exercise provides you with powerful protection against cardiovascular and metabolic diseases. However, the exact molecular mechanisms that link regular activity to improved health are unclear. A study published April 14 in Advancement in sciences makes great gains in this understanding. Building on previous work on individual training sessions, researchers at Ghent University in Belgium found that long-term exercise activates histamine receptors, which improves a variety of cardiometabolic risk factors, from insulin sensitivity to aerobic capacity to blood vessel health.
“It’s great, it’s very cool work,” says University of Oregon exercise physiologist John Halliwill, who was not involved in the study. “This is one of the few studies that is finally looking at these molecular converters, and this is the only study on histamine that has shown it to have a lasting impact on how we adapt to exercise. . . . It is not just a signal related to allergies and asthma, wound healing. It seems to have a hand in everything movement related which is pretty amazing. “
Histamine is typically linked to allergic reactions and gastric acid secretion, but in recent years Halliwill and others have shown that histamine H is blocked1 and H.2 Receptors reduce muscular blood flow to people during recovery from a single workout. Blocking histamine receptors also changes the transcription of about a quarter of the genes, which are expressed differently after exercise, Halliwill says. Taken together, the results indicate that histamine is a positive mediator for the effects of exercise.
Exercise physiologist Wim Derave from the University of Ghent in Belgium and his PhD student Thibaux Van der Stede wanted to know whether histamine also plays a role in long-term exercise training that has known health benefits. They included 20 healthy men who did not participate in high-intensity interval training (HIIT) three times a week for six weeks. One hour before each training session, half of the men were given H-blocked drugs1 and H.2 Histamine receptors and the other half received a placebo. The histamine blockers were a combination of a common allergy drug, fexofenadine, which blocks the H.1 Receptor and either ranitidine, an acid-reducing drug that the US Food and Drug Administration withdrew from the market last year, or the antacid famotidine, both of which block H.2. The doses were higher than those taken to treat allergies or acid reflux.
The result showed that when we blocked the histamine receptors, many of the beneficial effects of exercise were compromised.
– Thibaux Van der Stede, Ghent University
The team found that after six weeks of training, men whose histamine receptors were blocked showed significantly less improvement in various parameters related to exercise performance, as well as less improvement in the mitochondrial ability to produce energy, than those who received a placebo. When the researchers gave the men glucose tolerance tests before and after the six-week exercise, they found that in men on placebo, insulin’s ability to move glucose from the bloodstream to the cells improved after exercise, but no improvement after exercise showed men on histamine blockers. Treated participants also had less capillary formation in their leg muscles, due to poorer microvasculature health, and no increase in endothelial nitric oxide synthase, which is critical to healthy endothelial cell function, after six weeks of training compared to placebo men.
“The result showed that when we blocked the histamine receptors, many of the positive effects of exercise were impaired,” says Van der Stede. “It really is the first time we’ve seen histamine be involved in any of these processes.”
“This is a really nice piece of basic human research,” says Mayo Clinic physiologist Michael Joyner, who did not take part in the study. “Any time you find a target that does multiple things, it’s the most interesting thing, and that those things are part of a series of adaptations for acute and chronic exercise is very, very interesting.”
Understanding the specific molecular effects of exercise training is important for many reasons, but one of the most important things you can do is to optimize your training plan. “It might be helpful if we understand which type of exercise is better than another at releasing histamine, which could help us improve the workout or improve health with an exercise prescription,” says Derave.
In addition, it is important to understand if certain drugs or supplements are interfering with the benefits of exercise. In this study, while the researchers gave subjects a combination of commonly used drugs to block two of the four histamine receptors, most people do not take both at the same time and not at the high concentrations the team used in the study. Derave also notes that it is unclear whether the same deleterious effects would occur if the study only blocked one of the receptors. “We can’t be entirely sure what relevance this has,” says Derave, “but it may be that people who train for sport or health don’t get the full bang for their money because they are also using drugs. This is an issue and should be explored in further studies. “
Another direction in the future will be to confirm these results in women, says Derave. Although he and his colleagues included women in an initial study of acute exercise, the current study only included men. “We should still confirm this with women,” says Derave. Halliwill agrees. “For too long we have not included enough women in our studies to be able to definitively say that men and women behave differently in response to this intervention or these stimuli.”
T. Van der Stede et al., “Histamine H1 and H2 receptors are essential converters of the integrative training response in humans”. Sci Adv7, eabf2856, 2021.
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