Transforming growth factor β1 impairs the transcriptomic response to contraction in myotubes from women with polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is characterised by a hormonal imbalance affecting the reproductive and metabolic health of reproductive‐aged women. Exercise is recommended as a first‐line therapy for women with PCOS to improve their overall health; however, women with PCOS are resistant to the metabolic benefits of exercise training. Here, we aimed to gain insight into the mechanisms responsible for such resistance to exercise in PCOS. We employed an in vitro approach with electrical pulse stimulation (EPS) of cultured skeletal muscle cells to explore whether myotubes from women with PCOS have an altered gene expression signature in response to contraction. Following EPS, 4719 genes were differentially expressed (false discovery rate <0.05) in myotubes from women with PCOS compared to 173 in healthy women. Both groups included genes involved in skeletal muscle contraction. We also determined the effect of two transforming growth factor β (TGFβ) ligands that are elevated in plasma of women with PCOS, TGFβ1 and anti‐Müllerian hormone (AMH), alone and on the EPS‐induced response. While AMH (30 ng/ml) had no effect, TGFβ1 (5 ng/ml) induced the expression of extracellular matrix genes and impaired the exercise‐like transcriptional signature in myotubes from women with and without PCOS in response to EPS by interfering with key processes related to muscle contraction, calcium transport and actin filament. Our findings suggest that while the fundamental gene expression responses of skeletal muscle to contraction is intact in PCOS, circulating factors like TGFβ1 may be responsible for the impaired adaptation to exercise in women with PCOS. Key points Gene expression responses to in vitro contraction (electrical pulse stimulation, EPS) are altered in myotubes from women with polycystic ovary syndrome (PCOS) compared to healthy controls, with an increased expression of genes related to pro‐inflammatory pathways. Transforming growth factor β1 (TGFβ1) upregulates genes related to extracellular matrix remodelling and reduces the expression of contractile genes in myotubes, regardless of the donor's health status. TGFβ1 alters the gene expression response to EPS, providing a possible mechanism for the impaired exercise adaptations in women with PCOS.

Identification of Key Genes Associated With Pcos (Poly Cystic Ovarian Syndrome) and Endometrial/Ovarian Cancer Through Bioinformatics

“…For our study, we analyzed three distinct microarray datasets from the Gene Expression Omnibus (GEO) database hosted by the NCBI. These datasets corresponded to PCOS, endometrial cancer, and ovarian cancer, identified by the accession numbers GSE199225[12], GSE215413[13], and GSE174670[14], respectively. Our selection criteria included considering only complete samples categorized as either cases or controls.…”

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

“…NGS dataset GSE199225 [25] was acquired from the GEO database. The GSE199225 profile was composed of 30 PCOS samples and 30 normal control samples.…”

“…We chosen NGS dataset GSE199225 [25] from Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) [26] database. We then applied for DESeq2 package in R software to obtain the differentially expressed genes (DEGs) in the NGS dataset.…”

Mimicking exercise in vitro: effects of myotube contractions and mechanical stretch on omics

“…Two recent studies examined the transcriptome after EL-EPS in primary human myotubes (25,26). Genes related to pro-inflammatory pathways were upregulated in myotubes originating from females with polycystic ovary syndrome relative to healthy controls (25).…”

“…Two recent studies examined the transcriptome after EL-EPS in primary human myotubes (25,26). Genes related to pro-inflammatory pathways were upregulated in myotubes originating from females with polycystic ovary syndrome relative to healthy controls (25). Although EL-EPS responses may be affected by donor characteristics (1,3), a recent study suggests that age, sex, and EL-EPS parameters may not have substantial transcriptomic and proteomic effects (26).…”