Proteomic analysis shows decreased type I fibers and ectopic fat accumulation in skeletal muscle from women with PCOS

• Published in: eLife Vol. 12
• Main Authors: Stener-Victorin, Elisabet, Eriksson, Gustaw, Mohan Shrestha, Man, Rodriguez Paris, Valentina, Lu, Haojiang, Banks, Jasmine, Samad, Manisha, Perian, Charlène, Jude, Baptiste, Engman, Viktor, Boi, Roberto, Nilsson, Emma, Ling, Charlotte, Nyström, Jenny, Wernstedt Asterholm, Ingrid, Turner, Nigel, Lanner, Johanna, Benrick, Anna
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 05-01-2024; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Abdomen; Acupuncture; Adipocytes; Adipose Tissue; Adipose tissues; Androgen receptors; Androgens; Animals; Basic Medicine; Biopsy; Body fat; Clinical Medicine; DNA methylation; Down-regulation; Electrical stimuli; Electroacupuncture; Epigenetics; Extracellular matrix; Fatty acids; Female; Filaments; Fysiologi; Gene expression; Genes; genetics; Genetics and Genomics; genomics; Glucose; Human; Humans; Insulin resistance; Klinisk medicin; Lipids; Mass spectrometry; Mass spectroscopy; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicinska och farmaceutiska grundvetenskaper; Metabolic disorders; Metabolic pathways; Metabolism; Methylation; Mice; Mouse; Muscle contraction; Muscle, Skeletal; Muscles; Musculoskeletal system; Obesity; Ovaries; Overweight; PCOS; Phosphorylation; Physiology; Polycystic Ovary Syndrome; Proteins; Proteomics; Scientific equipment and supplies industry; Scientific imaging; Skeletal muscle; Stein-Leventhal syndrome; transcriptomics; Translational Medicine TRIM; Translationell medicin TRIM; Type 2 diabetes; Women; Wound healing; United States; Sweden; mouse; PCOS; genetics; proteomics; methylation; adipose tissue; transcriptomics; genomics; medicine; skeletal muscle; human
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.87592

Polycystic ovary syndrome's (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead to changes in protein levels and biological function.
To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry, and analyzed gene expression and methylation. Adipose tissue and skeletal muscle were collected at baseline from 10 women with and without PCOS, and in women with PCOS after 5 weeks of treatment with electrical stimulation.
Perilipin-1, a protein that typically coats the surface of lipid droplets in adipocytes, was increased whereas proteins involved in muscle contraction and type I muscle fiber function were downregulated in PCOS muscle. Proteins in the thick and thin filaments had many altered phosphorylation sites, indicating differences in protein activity and function. A mouse model was used to corroborate that androgen exposure leads to a shift in muscle fiber type in controls but not in skeletal muscle-specific androgen receptor knockout mice. The upregulated proteins in muscle post treatment were enriched in pathways involved in extracellular matrix organization and wound healing, which may reflect a protective adaptation to repeated contractions and tissue damage due to needling. A similar, albeit less pronounced, upregulation in extracellular matrix organization pathways was also seen in adipose tissue.
Our results suggest that hyperandrogenic women with PCOS have higher levels of extra-myocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading to insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective.
Swedish Research Council (2020-02485, 2022-00550, 2020-01463), Novo Nordisk Foundation (NNF22OC0072904), and IngaBritt and Arne Lundberg Foundation. Clinical trial number NTC01457209.