Cellular deconstruction of the human skeletal muscle microenvironment identifies an exercise-induced histaminergic crosstalk
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.
Authors
- Peter Van Eenoo (ORCID: https://orcid.org/0000-0002-0303-4922)
- Laurie De Wilde (ORCID: https://orcid.org/0000-0002-3472-2170)
- Guillermo Turiel (ORCID: https://orcid.org/0009-0007-9650-1553)
- Lasse Gliemann (ORCID: https://orcid.org/0000-0002-0382-2523)
- Jan Spaas (ORCID: https://orcid.org/0000-0002-4953-2505)
- Erik A. Richter (ORCID: https://orcid.org/0000-0002-6850-3056)
- Katrien De Bock (ORCID: https://orcid.org/0000-0001-8232-4663)
- Alexia Van de Loock (ORCID: https://orcid.org/0000-0002-3471-1869)
- Jasper Anckaert (ORCID: https://orcid.org/0000-0001-8144-4639)
- Max Ullrich (ORCID: https://orcid.org/0009-0002-3079-6110)
- Siska Croubels (ORCID: https://orcid.org/0000-0001-6357-3517)
- Camilla Collin Hansen (ORCID: https://orcid.org/0000-0003-2839-6150)
- Ylva Hellsten (ORCID: https://orcid.org/0000-0002-2435-9558)
- Justine Nuytens (ORCID: https://orcid.org/0000-0002-4878-1200)
- Eline Lievens (ORCID: https://orcid.org/0000-0003-2549-3369)
- Ruud Van Thienen
- John R. Halliwill (ORCID: https://orcid.org/0000-0003-3001-1715)
- Wim Derave (ORCID: https://orcid.org/0000-0002-2225-5587)
- Pieter Mestdagh (ORCID: https://orcid.org/0000-0001-7821-9684)
- Anneleen Weyns
- Thibaux Van der Stede (ORCID: https://orcid.org/0000-0003-2038-2504)
- Andrea Tamariz‐Ellemann (ORCID: https://orcid.org/0000-0002-1554-6802)
- Nurten Yigit (ORCID: https://orcid.org/0000-0003-1183-8688)
- Jo Vandesompele (ORCID: https://orcid.org/0000-0001-6274-0184)
- Siegrid De Baere
Institutions
- University of Copenhagen (DK)
- University of Oregon (US)
- Ghent University (BE)
- ETH Zurich (CH)
- Hasselt University (BE)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2025-02-06
- DOI
- https://doi.org/10.1016/j.cmet.2024.12.011
- Citations
- 14
- Primary Topic
- Muscle Physiology and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- Fonds Wetenschappelijk Onderzoek
- Universiteit Gent
- Vlaamse regering