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Estrogen weakens muscle endurance via estrogen receptor-p38 MAPK-mediated orosomucoid (ORM) suppression

2018; Springer Nature; Volume: 50; Issue: 3 Linguagem: Inglês

10.1038/emm.2017.307

2092-6413

Yang Sun, Zhen Qin, Jingjing Wan, Peng‐Yuan Wang, Yili Yang, Jian‐Guang Yu, Bo‐Han Hu, Ding‐Feng Su, Zhu‐Min Luo, Xia Liu,

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Gender differences in fatigue manifest as females being more prone to feel exhaustion and having lower muscle endurance. However, the mechanisms of these effects remain unclear. We investigated whether orosomucoid, an endogenous anti-fatigue protein that enhances muscle endurance, is involved in this regulation. Female rats exhibited lower muscle endurance, and this gender difference disappeared in orosomucoid-1-deficient mice. Female rats also exhibited weaker orosomucoid induction in serum, liver and muscle in response to fatigue compared with male rats. Ovariectomy elevated orosomucoid levels and increased swimming time, and estrogen replenishment reversed these effects. Exogenous estrogen treatment in male and female mice produced opposite effects. Estrogen decreased orosomucoid expression and its promoter activity in C2C12 muscle and Chang liver cells in vitro, and estrogen receptor or p38 mitogen-activated protein kinase blockade abolished this effect. Therefore, estrogen negatively regulates orosomucoid expression that is responsible for the weaker muscle endurance in females. Weaker muscle endurance in female rats than in males is linked to estrogen reducing production of the protein orosomucoid. This protein is known to enhance muscle endurance and hence delay the onset of fatigue. Researchers in China led by Xia Liu and Zhu-Min Luo at the Second Military Medical University in Shanghai found that deleting the gene for orosomucoid in female rats removed the gender difference in muscle endurance. They found evidence of a role for estrogen by studying females after ovary removal, and by investigating the effects of estrogen supplementation. Experiments with cultured muscle and liver cells revealed that estrogen inhibits the activity of the gene for orosomucoid. The significance of these findings in humans should be investigated. There may be implications for understanding and treating conditions such as chronic fatigue syndrome.