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Adipocyte and Cell Biology

The impact of mild hypoxia exposure on myokine secretion in human obesity

International Journal of Obesity volume 47, pages 520–527 (2023)Cite this article

Subjects

Abstract

Background/Objective

Compelling evidence indicates that myokines act in an autocrine, paracrine and endocrine manner to alter metabolic homeostasis. The mechanisms underlying exercise-induced changes in myokine secretion remain to be elucidated. Since exercise acutely decreases oxygen partial pressure (pO2) in skeletal muscle (SM), the present study was designed to test the hypothesis that (1) hypoxia exposure impacts myokine secretion in primary human myotubes and (2) exposure to mild hypoxia in vivo alters fasting and postprandial plasma myokine concentrations in humans.

Methods

Differentiated primary human myotubes were exposed to different physiological pO2 levels for 24 h, and cell culture medium was harvested to determine myokine secretion. Furthermore, we performed a randomized single-blind crossover trial to investigate the impact of mild intermittent hypoxia exposure (MIH: 7-day exposure to 15% O2, 3x2h/day vs. normoxia: 21% O2) on in vivo SM pO2 and plasma myokine concentrations in 12 individuals with overweight and obesity (body-mass index ≥ 28 kg/m2).

Results

Hypoxia exposure (1% O2) increased secreted protein acidic and rich in cysteine (SPARC, p = 0.043) and follistatin like 1 (FSTL1, p = 0.021), and reduced leukemia inhibitory factor (LIF) secretion (p = 0.009) compared to 3% O2 in primary human myotubes. In addition, 1% O2 exposure increased interleukin-6 (IL-6, p = 0.004) and SPARC secretion (p = 0.021), whilst reducing fatty acid binding protein 3 (FABP3) secretion (p = 0.021) compared to 21% O2. MIH exposure in vivo markedly decreased SM pO2 (≈40%, p = 0.002) but did not alter plasma myokine concentrations.

Conclusions

Hypoxia exposure altered the secretion of several myokines in primary human myotubes, revealing hypoxia as a novel modulator of myokine secretion. However, both acute and 7-day MIH exposure did not induce alterations in plasma myokine concentrations in individuals with overweight and obesity.

Clinical trials identifier: This study is registered at the Netherlands Trial Register (NL7120/NTR7325).

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Fig. 1: Effects of hypoxia on myokine secretion in human myotubes.
Fig. 2: Plasma myokine concentrations during high-fat mixed meal challenge.
Fig. 3: Plasma myokine concentrations following exposure regimen.
Fig. 4: Associations between skeletal muscle oxygen tension and plasma myokine concentrations.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank N. Hoebers and Y. Essers (Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+) for excellent technical support with cell culture experiments.

Funding

This study was funded supported by a Senior Fellowship grant from the Dutch Diabetes Research Foundation (awarded to GG, grant number: 2015.82.1818) to GG and a Rising Star Award Fellowship (2014) from the European Foundation for the Study of Diabetes to GG. The funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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Authors and Affiliations

  1. Department of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University Medical Center+, Maastricht, The Netherlands

    Rens L. J. van Meijel, Lars M. M. Vliex, Ellen E. Blaak & Gijs H. Goossens

  2. Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Medical Faculty, Duesseldorf, Germany

    Sonja Hartwig, Stefan Lehr & Hadi Al-Hasani

  3. German Center for Diabetes Research, Partner Duesseldorf, München-Neuherberg, Duesseldorf, Germany

    Sonja Hartwig, Stefan Lehr & Hadi Al-Hasani

Authors
  1. Rens L. J. van Meijel
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Contributions

RVM, EB, and GG were responsible for the conceptualization and design of the studies. RVM, LV, and SH conducted the experiments, and contributed to data acquisition and analysis of data. GG acquired funding for the study. RVM wrote the paper, and LV, SH, SL, HAH, EB, and GG critically revised the paper. All authors approved the final version of the paper for publication. GG is guarantor of the work.

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Correspondence to Gijs H. Goossens.

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van Meijel, R.L.J., Vliex, L.M.M., Hartwig, S. et al. The impact of mild hypoxia exposure on myokine secretion in human obesity. Int J Obes 47, 520–527 (2023). https://doi.org/10.1038/s41366-023-01294-5

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