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. 2026 Feb 20.
doi: 10.1007/s00125-026-06684-8. Online ahead of print.

Thromboxane signalling links immune activation to enhanced glucose uptake in skeletal muscle

Ahmed M Abdelmoez #  1 , Maxence Jollet #  2 , Xue Yu #  1 , David Rizo-Roca  1 , Alesandra A Marica  1 , Joaquin Ortiz de Zevallos  2 , Lucile Dollet  1 , Melissa L Borg  1 , Marie Björnholm  2 , Antonio Checa  3 , Tommy Olsson  4 , Julia Otten  4 , Juleen R Zierath  1   2 , Anna Krook  1 , Thue W Schwartz  5 , Alexander V Chibalin  2 , Nicolas J Pillon  6
Affiliations

Thromboxane signalling links immune activation to enhanced glucose uptake in skeletal muscle

Ahmed M Abdelmoez et al. Diabetologia. .

Abstract

Aims/hypothesis: Exercise elicits a spectrum of metabolic and inflammatory responses that are crucial for skeletal muscle adaptation and overall health, particularly in the context of metabolic diseases, yet the contribution of prostanoid signalling to these processes remains unclear. We hypothesised that exercise-induced thromboxane production enhances skeletal muscle glucose uptake and improves whole-body glucose control.

Methods: Plasma prostanoids were quantified in men and women with normal glucose tolerance or type 2 diabetes before, immediately after and 3 h after a single bout of exercise. Cyclooxygenase (COX-2) transcript levels were evaluated in human skeletal muscle, whole blood, peripheral blood mononuclear cells and skeletal muscle-resident immune cells. Metabolic and transcriptomic effects of thromboxane receptor activation were analysed in mouse C2C12, rat L6 and human primary skeletal muscle cells. Glucose tolerance in vivo was assessed following i.p. administration of the thromboxane receptor agonist I-BOP in male and female mice. Tissue-specific glucose uptake was quantified by measuring radiolabelled 2-deoxyglucose incorporation during an IVGTT.

Results: Acute exercise increased plasma thromboxane B₂ concentrations and skeletal muscle mRNA levels of PTGS2 (encoding COX-2) selectively in monocyte/macrophage populations. In skeletal muscle cells, the thromboxane receptor agonist I-BOP increased glucose uptake in a dose-dependent manner up to 2.5-fold within 4 h and enhanced glycogen synthesis by 430%. Transcriptomic and signalling analysis revealed activation of protein kinase A and cytoskeletal remodelling pathways linked to GLUT4 trafficking. In vivo, I-BOP improved glucose tolerance in male mice in a dose-dependent manner, without altering insulin levels. Thromboxane receptor stimulation increased glucose uptake in extensor digitorum longus muscle by 43%. Importantly, thromboxane receptor activation preserved its glucose-lowering efficacy in diet-induced obese male mice.

Conclusions/interpretation: Exercise induces skeletal muscle-derived thromboxane production through macrophage-specific COX-2 activation. Thromboxane receptor stimulation enhances glucose uptake and glycogen storage via cytoskeletal remodelling, partially mimicking the acute exercise transcriptomic response. In vivo, thromboxane receptor activation improves glucose tolerance and skeletal muscle glucose uptake, with preserved efficacy in obesity. These findings identify thromboxane signalling as a previously unrecognised immunometabolic axis linking inflammation to glucose regulation and highlight the thromboxane receptor as a potential therapeutic target for metabolic disease.

Keywords: Exercise; Glucose; Metabolism; Skeletal muscle; Thromboxane; Type 2 diabetes.

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Conflict of interest statement

Acknowledgements: We would like to thank BEA, the Bioinformatics and Expression Analysis core facility, which is supported by the board of research at the Karolinska Institutet, and the Karolinska Institutet Small Molecule Mass Spectrometry Core Facility (KI-SMMS), financed by the Infrastructure Board at Karolinska Institutet, for support for sample analyses and scientific input. The computations were enabled by resources in project NAISS 2023/22-466 provided by the National Academic Infrastructure for Supercomputing in Sweden (NAISS) at UPPMAX, funded by the Swedish Research Council through grant agreement no. 2022-06725. We thank C. Pillon Hue ( https://cpillonhue.art/ ) for the design of the graphical abstract. Data availability: Data supporting the findings shown in Fig. 1 are available within the paper and its ESM. Other data are available from the corresponding author on reasonable request. Funding: Open access funding provided by Karolinska Institute. This study was supported by grants from AstraZeneca SciLifeLab Research Programme, Knut and Alice Wallenberg Foundation (KAW 2023.0312 to JRZ), Swedish Research Council (2022-00609 to AK; 2015-00165 to JRZ), the Novo Nordisk Foundation (NNF22OC0077741, NNF24SA0092609 to JRZ), the Swedish Diabetes Foundation (DIA2021-641 to AK; DIA2023-824 to JRZ), the European Research Council (ERC-2023-AdG 101142093 to JRZ) and Region Stockholm (ALF project, to JRZ) for the clinical interventions. NJP holds a future leader award from the Novo Nordisk Foundation and European Foundation for the Study of Diabetes (NNF/EFSD NNF21SA0072747) and a grant from the Diabetes Wellness Network Sverige (PG21-6524). AK holds a Distinguished Investigator Grant within Endocrinology and Metabolism from the Novo Nordisk Foundation (NNF24OC0088739). DRR holds an Excellence Emerging Investigator Grant from Novo Nordisk (NNF25OC0101637). JOdZ is supported by a postdoctoral fellowship from the Strategic Research Program in Diabetes at Karolinska Institutet. TO is a fellow of the Stellenbosch Institute for Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, South Africa. The Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR) is an independent research centre at the University of Copenhagen, partially funded by an unconditional donation from the Novo Nordisk Foundation (NNF18CC0034900, NNF23SA0084103). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Authors’ relationships and activities: TO and AK are members of the editorial board of Diabetologia. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. Contribution statement: AMA and NJP conceived and designed the study. Experimental investigations and data collection were performed by AMA, MJ, XY, DRR, AAM, JOZ, LD, MB, AC, AVC and NJP. Formal data analysis was carried out by AMA, MJ, XY, AC and NJP, with validation performed by XY, MJ and NJP. The study was supervised by AK, JRZ, TS, AVC and NJP, and funding was acquired by NJP, AK and JRZ. Data visualisation was conducted by AMA, MJ, XY and NJP. The original manuscript draft was written by AMA and NJP, and all authors contributed to reviewing and editing the manuscript. All authors have discussed the results and take responsibility for the underlying data, provided intellectual inputs into aspects of this study and agree to its submission for publication. NJP is responsible for the integrity of the work as a whole.

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