Exercise-induced irisin improves follicular dysfunction by inhibiting IRE1α-TXNIP/ROS-NLRP3 pathway in PCOS

J Ovarian Res. 2023 Jul 31;16(1):151. doi: 10.1186/s13048-023-01242-x.

Abstract

Background: Excessive production of androgen drives oxidative stress (OS) and inflammasome activation in ovarian granulosa cells (GCs). Therefore, the induced follicular developmental disorder is the major cause of infertility in women with polycystic ovary syndrome (PCOS). Exercise-induced upregulation of irisin is capable of regulating metabolism by reducing OS and inflammation. Exercise has been shown to alleviate a range of PCOS symptoms, including maintaining a normal menstrual cycle, in several clinical trials.

Methods: Female Sprague-Dawley (SD) rats and primary ovarian cells were treated with two different androgens, dehydroepiandrosterone (DHEA) and dihydrotestosterone (DHT), to simulate a hyperandrogenic environment, followed by eight weeks of exercise training and irisin intervention. The levels of reactive oxygen species (ROS), tissue inflammation and fibrosis were examined using hematoxylin and eosin (H&E) staining, western blot, quantitative real-time PCR (qRT-PCR), dichlorofluorescein diacetate (DCF-DA) probe detection, immunofluorescence staining, immunohistochemistry, and Sirius red staining.

Results: Exercise for eight weeks improved polycystic ovarian morphology and decreased the levels of inflammation, OS, and fibrosis in PCOS rats. Hyperandrogen increased ROS production in ovarian cells by inducing endoplasmic reticulum stress (ERS) and activating the inositol-requiring enzyme 1α (IRE1α)-thioredoxin-interacting protein (TXNIP)/ROS-NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway, further enhancing the levels of inflammation. Irisin suppressed the expression of IRE1α and its downstream targets, thus improving the ovarian dysfunction of PCOS rats induced by hyperandrogen.

Conclusion: Exercise can alleviate various phenotypes of PCOS rats induced by DHEA, and its therapeutic effect may be mediated by secreting beneficial myokines. IRE1α may be an important target of irisin for reducing OS and inflammation, thereby improving ovarian fibrosis.

Keywords: Exercise; Follicular dysfunction; IRE1α-TXNIP/ROS-NLRP3; Irisin; PCOS.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Dehydroepiandrosterone
  • Endoribonucleases / metabolism
  • Endoribonucleases / therapeutic use
  • Female
  • Fibronectins / metabolism
  • Fibrosis
  • Humans
  • Inflammation / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Polycystic Ovary Syndrome* / drug therapy
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism

Substances

  • Reactive Oxygen Species
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Endoribonucleases
  • Fibronectins
  • Protein Serine-Threonine Kinases
  • Dehydroepiandrosterone
  • TXNIP protein, human
  • Carrier Proteins
  • TXNIP protein, rat
  • Cell Cycle Proteins