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Role of plasminogen activator inhibitor-1 in glucocorticoid-induced muscle change in mice

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Abstract

We recently revealed that plasminogen activator inhibitor-1 (PAI-1), a serine protease inhibitor, is involved in diabetes, osteoporosis and muscle wasting induced by glucocorticoid (GC) treatment in mice. In the present study, we investigated the detailed mechanisms by which GC induces muscle wasting through PAI-1 in vivo and in vitro. PAI-1 deficiency suppressed the mRNA levels of atrogin1 and muscle RING-Finger Protein 1 (MuRF1), ubiquitin ligases leading to muscle degradation, elevated by GC treatment in the gastrocnemius muscle of mice. In vitro study revealed that active PAI-1 treatment augmented the increase in atrogin1 mRNA levels enhanced by dexamethasone (Dex) in mouse myoblastic C2C12 cells. Moreover, a reduction in endogenous PAI-1 level by siRNA suppressed the mRNA levels of atrogin1 and MuRF1 enhanced by Dex in C2C12 cells. In contrast, a reduction in endogenous PAI-1 levels and active PAI-1 did not affect the phosphorylations of Akt and p70S6 kinase nor myogenic differentiation with or without Dex in C2C12 cells. In addition, PAI-1 deficiency blunted IGF-1 mRNA levels decreased by GC treatment in the gastrocnemius muscle of mice, although neither active PAI-1 nor a reduction in endogenous PAI-1 levels affected the levels of IGF-1 mRNA in C2C12 cells in the presence of Dex. In conclusion, our data suggest that paracrine PAI-1 is involved in GC-induced muscle wasting through the enhancement of muscle degradation in mice.

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Acknowledgements

The study was supported by grants-in-aid for scientific research 16K10924 and 15K08220 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to Y.T. and H.K., respectively) and grants from the Takeda Science Foundation and the Osaka Medical Research Foundation for Intractable Diseases.

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Authors and Affiliations

  1. Department of Physiology and Regenerative Medicine, Faculty of Medicine, Kindai University, 377-2 Ohnohigashi, Osakasayama, Osaka, 589-8511, Japan

    Yukinori Tamura, Naoyuki Kawao, Takeshi Shimoide, Kiyotaka Okada, Osamu Matsuo & Hiroshi Kaji

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  1. Yukinori Tamura
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  2. Naoyuki Kawao
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  3. Takeshi Shimoide
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  4. Kiyotaka Okada
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  5. Osamu Matsuo
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  6. Hiroshi Kaji
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Correspondence to Hiroshi Kaji.

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Tamura, Y., Kawao, N., Shimoide, T. et al. Role of plasminogen activator inhibitor-1 in glucocorticoid-induced muscle change in mice. J Bone Miner Metab 36, 148–156 (2018). https://doi.org/10.1007/s00774-017-0825-8

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  • DOI: https://doi.org/10.1007/s00774-017-0825-8

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