Histamines are Crucial for Exercise Training Benefits

Exercise is perhaps the strongest and most potent disease-reduction strategy that we know of. 

Aerobic, and to a lesser extent resistance exercise training causes all sorts of beneficial adaptations in our body including improved metabolic function, increased muscle mass and reduced body fat, more mitochondria, and enhanced blood vessel health.

Separately and together, these adaptations reduce our risk for chronic diseases and are likely a sure-fire way to live better and longer.

A looming question in the field of exercise physiology has been how these benefits of exercise are communicated at a cellular level. What specific molecular mechanisms mediate the integrative adaptive response to exercise?

We know that a variety of signaling molecules are released during exercise (these are termed ‘myokines’). However, might one particular system or group of molecules regulate the exercise training response to a larg(er) degree?

Perhaps. A new study published in the journal Science Advances proposes that histamines, molecules released by our immune system, might play a major, if not critical role, in transducing the benefits of exercise.

Histamines are usually talked about in reference to allergic reactions — one might take an antihistamine to reduce allergy-related symptoms. These drugs work by blocking the release of histamines, thereby reducing the immune/inflammatory responses associated with common allergens.

How do these molecules relate to exercise? It has been known for some time that a single bout of acute exercise (specifically, muscle contraction) can cause the release of histamines, and histamines also play a role in sustaining post-exercise blood flow to muscles.

Whether histamines are also responsible for mediating adaptations to long-term exercise training however, has never been investigated. Therefore, the purpose of this study was to evaluate the role of histamine signaling for exercise-training induced adaptations in a variety of body systems.

Basically, the question was: “Does blocking histamine signaling during exercise training prevent some of the adaptations to training? If so, where, and to what extent?”

Brief study methods

This study had two parts: an acute study and a chronic study.

For the acute study, participants (8) completed a single bout of cycling exercise with and without histamine receptor (H1/H2) blockade. Before and after exercise, heart rate, blood flow, and blood pressure were measured to determine the role of histamines in the post-exercise cardiovascular response.

For the chronic study, participants (20) completed 6-weeks of exercise training (3 days per week of cycling exercise). One group of participants completed training with chronic blockade of the histamine H1 and H2 receptors, and one group completed training with a placebo (i.e. no histamine receptor blockade, i.e. the control group).

Measures of exercise capacity (maximal and submax exercise performance), mitochondrial capacity and function, metabolic health (glucose tolerance and insulin sensitivity), and vascular function were assessed pre and post training, as well as halfway through the training program.



Below is a summary of some of the main study findings, grouped by outcome category.

Acute study

– Post-exercise muscle perfusion (blood flow) was significantly reduced in the H1/H2 receptor blockade group. This means that histamine signaling is important for regulating post-exercise blood flow.

Chronic study

Exercise capacity and mitochondrial function

– Maximal exercise capacity (VO2 max) improved in both groups after training

– Peak power output increased in both groups, but was higher in the control group vs. the histamine receptor blockade group

– Submaximal exercise efficiency was improved in the control group, but not in the histamine blockade group

Mitochondrial capacity was increased more in the control group vs. the histamine blockade group

Antioxidant capacity increased in the control group, but not the histamine blockade group

 Metabolic function

Blood glucose and insulin levels were improved in the control group, but not the histamine blockade group

Glucose tolerance was improved in the control, but not in the histamine blockade group

 Vascular function

– Exercise training improved leg vascular function and muscle capillary number only in the control group. The histamine blockade group experienced no exercise-related improvement in vascular function

– Expression of the enzyme responsible for producing nitric oxide (NO) was increased in the control group, but not the histamine blockade group

I presented a lot of results here, so let’s summarize the findings with a few key points from the paper:

1. Histamines play an essential role in mediating the improvements in mitochondrial and antioxidant capacity in response to exercise training.

2. Exercise-induced metabolic adaptations in glucose control and insulin action are partially dependent on histamine signaling.

3. Histamines are necessary for the exercise-induced improvements in vascular function, muscle capillary content, and eNOS enzyme levels.

This is probably one of the most interesting papers that I’ve read in quite some time, for a couple of reasons.

First of all, much talk around exercise lately has centered around the ‘proteomic’ response to exercise. New techniques have allowed us to quantify the molecular response to exercise, revealing that thousands of unique molecules are released in response to a single exercise bout. 

To see evidence of significant impairments in exercise adaptations when just one signaling cascade (in this case, histamine H1/H2 signaling) is blocked is pretty noteworthy and, to be honest, quite surprising.

Secondly, this can (re)stimulate a discussion about drug development. “Exercise mimetics” are (in theory) pills that we could take to ‘mimic’ the effects of exercise. If histamines play such a role in the integrative exercise response, perhaps a histamine receptor-stimulating drug, or a cocktail containing such ingredients, could be used therapeutically to boost health and function in people unable (or unwilling) to exercise.

I’m not hopeful that we will ever have “exercise in a pill” — it just doesn’t seem reasonable (or preferable, for that matter) that one drug will perfectly replicate the integrative nature of exercise.

However, with a more complete understanding of how exercise regulates adaptations at the molecular level, we are definitely getting closer to that reality. In terms of chronic disease treatment, this could be paradigm-shifting.

For now, breaking a sweat is still the best option for your health, and you can partly thank your histamine system for that.

Study cited

Van der Stede T, Blancquaert L, Stassen F, et al. Histamine H 1 and H 2 receptors are essential transducers of the integrative exercise training response in humans. Sci Adv. 2021;7(16):eabf2856. doi:10.1126/sciadv.abf2856

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