Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk,2025,Van der Stede et al

Highlights

Mononuclear cells are primary drivers of the exercise response in skeletal muscle
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Release of histamine from skeletal muscle during exercise from mast cells
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Histamine receptor antagonists impair post-exercise muscle glycogen resynthesis
•
Exercise-induced transcriptional activation of inflammatory signaling by histamine

Summary
Plasticity of skeletal muscle is induced by transcriptional and translational events in response to exercise, leading to multiple health and performance benefits. The skeletal muscle microenvironment harbors myofibers and mononuclear cells, but the rich cell diversity has been largely ignored in relation to exercise adaptations.

Using our workflow of transcriptome profiling of individual myofibers, we observed that their exercise-induced transcriptional response was surprisingly modest compared with the bulk muscle tissue response. Through the integration of single-cell data, we identified a small mast cell population likely responsible for histamine secretion during exercise and for targeting myeloid and vascular cells rather than myofibers.

We demonstrated through histamine H1 or H2 receptor blockade in humans that this paracrine histamine signaling cascade drives muscle glycogen resynthesis and coordinates the transcriptional exercise response.

Altogether, our cellular deconstruction of the human skeletal muscle microenvironment uncovers a histamine-driven intercellular communication network steering muscle recovery and adaptation to exercise.
LINK

Shows that mast cells release histamine during skeletal muscle exercise which acts on other immune cells, driving an inflammatory program that favors muscle glycogen resynthesis

 

A few quotes that I highlighted —

Spoiler

• knowledge on most of the canonical exercise-induced genes is insufficient.

• introduction of various single-cell omics technologies in skeletal muscle research has been transforming our view on the heterogeneity and importance of mononuclear non-muscle cells

• Mast cells, a myeloid cell type that has been largely overlooked in relation to skeletal muscle, might be one cell type involved in exercise-induced intercellular crosstalk.

• identified a small mast cell population alongside a potent paracrine histamine release in human muscle during exercise

• Mast cells are granulocytes and tissue-residing upon differentiation, but little is known about their specific role in skeletal muscle, especially in relation to exercise responses.

• Histamine is mainly known for its role in allergies, although we and others have previously shown that the histamine signaling system also plays an essential role in driving the adaptive chronic response (aerobic capacity, insulin sensitivity, and microvascular function) to exercise training in humans.

• H1 and H2 receptors are the main drivers for histamine signaling in skeletal muscle

• data show a clear and consistent local release of histamine into the muscle microenvironment upon exercise.

• an immune cell-mediated regulation of the skeletal muscle niche has been linked to glucose metabolism

• One of the hallmarks of muscle metabolic recovery after exhausting exercise is the capacity to replenish intracellular glycogen stores, which is dependent on optimal glucose delivery, uptake, and processing.

• resynthesis of glycogen during the 3-h recovery window, however, was impaired with H1 receptor blockade

• circulating levels of glucose and insulin were not affected

• histamine drives post-exercise muscle glycogen synthesis via H1 receptor signaling, independent of insulin-mediated activation of glycogen synthase and canonical insulin signaling.

• histamine receptor antagonism did not affect the exercise-induced temporal changes in circulating immune cells

• largest effects were observed during the recovery phase for both H1 and H2 blockade, consistent with the temporal pattern of immune cell activation and infiltration

• multiple inflammation-related pathways were downregulated with H1 blockade (interferon response, tumor necrosis factor alpha [TNF-a] signaling, IL-6-STAT3 signaling, inflammatory response).

• H1 blockade induced a downregulation of inflammation-related pathways, these pathways were positively enriched with H2 blockade.

• Divergent effects for H1 versus H2 blockade were also uncovered for inferred transcription factor activities (e.g., STAT3, STAT1, NFKB1, and TP53), with, in general, larger effects with H1 blockade

• Notable exceptions during recovery were an upregulation of TNF-a and p53 activity in placebo but downregulation with H1 and especially H2 blockade.

• while the immediate histamine signaling is of a paracrine nature between non-muscle mononuclear cells, the long-term muscle adaptations related to aerobic capacity, insulin sensitivity, and microvascular function are also dependent on this histamine signaling cascade.

• post-exercise perfusion of the muscle is blunted with histamine receptor blockade

• Overall, a major contribution of a small cell population such as mast cells is exciting since research on the role of mast cells in skeletal muscle is very scarce.

• Our results strongly suggest that modeling of intercellular communication patterns can discover new regulatory networks of interacting cells.

 

Reposted by one of the authors Thibaux Van der Stede last year

https://twitter.com/user/status/1841584753171947847


We have a question for LC and ME/CFS patients. If you have tried mast cell inhibitor drugs (such as mestinon, nalcrom, fexofenadine, famotidine), did you find them to reduce your long COVID PEM symptoms (threshold/duration)? Thanks, this helps our research a lot!

 

So no option ‘no effect’?

 

For me:
Can reduce some symptoms — does not reduce the deterioration of functional disability.

 

Which PEM threshold/duration level symptoms would it reduce?

 

None of those. Just helps with associated adrenaline and itchiness.