Evidence of a broad histamine footprint on the human exercise transcriptome

Abstract

Key pointsr Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity.r Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise.r We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine.r Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training.Abstract Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H 1 and H 2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H 1 and H 2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance.

The Intriguing Role of Histamine in Exercise Responses

“…Post-exercise inflammation has been associated with an elevation of neural growth factor (NGF) and glial derived nerve factor (GDNF), which likely contribute to the sensitization of Type III and IV afferent fibers in skeletal muscle (23, 35). Consistent with this possibility, these two transcripts were among the many that exhibited reduced expression at 3 h post-exercise in individuals taking combined histamine H 1 /H 2 -receptor antagonists relative to control conditions (33). This intriguing finding may explain part of the reduced pain sensitization and preservation of strength reported by Ely et al (12).…”

“…Muscle samples taken at different time points over the course of the exercise protocol suggest that the increase in skeletal muscle HDC varies with time (14). Similarly, Romero et al (33) found that HDC expression in skeletal muscle tissue increased after exercise in humans. In mice subjected to repeated bouts of walking, however, the exercise-induced increase in HDC expression in skeletal muscle tissue was reduced, perhaps due to a training adaptation (14).…”

“…The emerging evidence on histamine and exercise is that much of the early inflammatory response to exercise may be driven by this primordial signal molecule (33). What is currently unknown is whether this histaminergic component of post-exercise inflammation is necessary or permissive for exercise recovery broadly, or muscle repair specifically.…”

Induction of the Histamine-Forming Enzyme Histidine Decarboxylase in Skeletal Muscles by Prolonged Muscular Work: Histological Demonstration and Mediation by Cytokines

“…9,10) In humans, histamine H1-and H2-receptors have been shown to be involved in mediating post-exercise hyperemia and vasodilation in skeletal muscles. 11,12) These findings suggested that histamine might support PMW by maintaining or enhancing the functions of the microcirculation.…”

“…8) Recent studies suggest that histamine may play important physiological roles in skeletal muscles. [9][10][11][12] Interestingly, PMW induces HDC in skeletal muscles in mice. [13][14][15][16] However, published histological analyses of such HDC induction are lacking because appropriate anti-HDC antibodies have not previously been available.…”