Smoothelin-like protein 1 promotes insulin sensitivity and modulates the contractile properties of endometrial epithelial cells with insulin resistance

Front Endocrinol (Lausanne). 2024 May 31:15:1375771. doi: 10.3389/fendo.2024.1375771. eCollection 2024.

Abstract

Introduction: The incidence of infertility is significantly higher in women with diseases linked to impaired glucose homeostasis, such as insulin resistance. Defective glucose metabolism interferes with fertilization; however, the molecular mechanism underlying this interference is unclear. Smoothelin-like protein 1 (SMTNL1) was isolated from muscle and steroid hormone-responsive tissues and regulates the contractile functions of various cell types through the inhibition of myosin phosphatase (MP) holoenzyme. In addition, SMTNL-1 after phosphorylation at Ser301 by protein kinase A translocates to the nucleus and functions as a transcriptional co-activator of the progesterone receptor-B. SMTNL1 null mice exhibit reduced reproductive fitness and are more prone to type 2 diabetes mellitus. However, the role of SMTNL1 in endometrial epithelial cells is not known.

Methods: The effect of SMTNL1 overexpression was investigated in pregnancy and in gestational diabetic endometrial epithelial cell models by immunofluorescent staining, cell migration, and semi quantitative Western blot analysis and glucose uptake assay.

Results: We show that SMTNL1 promotes the differentiation of endometrial epithelial cells in a progesterone-dependent manner to attenuate insulin resistance. Furthermore, SMTNL1 hampers the migration capacity of epithelial cells in a gestational diabetes model by inhibiting the expression of MYPT1, the regulatory subunit of MP, and the activity of the holoenzyme, resulting in increased phosphorylation of the 20 kDa regulatory myosin light chain. SMTNL1 also acts as an insulin-sensitizing agent by increasing the gene expression of PP2A and DUPS9 protein phosphatases, resulting in decreased ERK1/2 activity and, hence, decreasing the phosphorylation of IRS-1 at Ser612 under gestational diabetes conditions.

Conclusion: SMTNL1 may have therapeutic relevance to the progesterone-dependent inhibition of endometrial epithelial cell migration under hyperglycemic conditions and insulin sensitivity in the endometrium in gestational diabetes or other metabolic disorders.

Keywords: endometrium; gene expression; insulin resistance; insulin signaling; migration.

MeSH terms

  • Animals
  • Cell Movement
  • Diabetes, Gestational / metabolism
  • Endometrium* / metabolism
  • Epithelial Cells* / metabolism
  • Female
  • Humans
  • Insulin Resistance*
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Muscle Proteins* / genetics
  • Muscle Proteins* / metabolism
  • Phosphorylation
  • Pregnancy

Substances

  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • SMTNL1 protein, mouse

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. Funding: This work was supported by grants from the National Research, Development and Innovation Office FK125043 and K143533 (to B. L.), the University of Debrecen, Faculty of Medicine Research Fund (1G3DBKJ0BFTK 247) for B. L. and from the EU co-financed by the European Regional Development Fund under project EFOP-3.6.2-16-2017-00006 and from the EFOP-3.6.3-VEKOP-16-2017-00009 project co-financed by EU. ÚNKP-22-3-1.