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Background: Polycystic ovary syndrome’s (PCOS) main feature is hyperandrogenism, which is linked to a higher risk of metabolic disorders in women. Gene expression analyses in adipose tissue and skeletal muscle reveal dysregulated metabolic pathways in women with PCOS, but these differences do not necessarily lead tochanges in protein levels and biological function. Methods: To advance our understanding of the molecular alterations in PCOS, we performed global proteomic and phosphorylation site analysis using tandem mass spectrometry. 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. Results: 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. 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. Conclusions: Our results suggest that hyperandrogenic women with PCOS have higher levels of extramyocellular lipids and fewer oxidative insulin-sensitive type I muscle fibers. These could be key factors leading insulin resistance in PCOS muscle while electric stimulation-induced tissue remodeling may be protective., CC BY 4.0 DEED5 January 2024Corresponding author: Anna Benrick, University of Gothenburg, Institute of Neuroscience and Physiology, Department of Physiology, Box 432, 405 30 Gothenburg, Sweden. Phone: +46 (0)709490148. E-mail: anna.benrick@gu.seFunding: A.B. holds funding from the Swedish Research Council (2020-02485), E.SV. holds funding from the Swedish Research Council (2022-00550), the Novo Nordisk Foundation (NNF22OC0072904), and I.W.A. holds funding from the Swedish Research Council (2020-01463), Mary von Sydow Foundation, Diabetes Wellness Sverige, and EFSD//European Research Programme on ‘New Targets for Diabetes or Obesity-related Metabolic Diseases’ supported by MSD 2022, and J.N. holds funding from IngaBritt and Arne Lundberg Research Foundation.Manuskript i medRxiv: DOI: 10.1101/2023.03.08.23286896

Women with polycystic ovary syndrome (PCOS) exhibit sustained elevation incirculating androgens during pregnancy, an independent risk factor linked topregnancy complications and adverse outcomes in offspring. Yet, furtherstudies are required to understand the effects of elevated androgens on celltype-specific placental dysfunction and fetal development. Therefore, aPCOS-like mouse model induced by continuous androgen exposure isexamined. The PCOS-mice exhibited impaired placental and embryonicdevelopment, resulting in mid-gestation lethality. Co-treatment with theandrogen receptor blocker, flutamide, prevents these phenotypes includinggerm cell specification . Comprehensive profiling of the placenta bywhole-genome bisulfite and RNA sequencing shows a reduced proportion oftrophoblast precursors, possibly due to the downregulation of Cdx2expression. Reduced expression of Gcm1, Synb, and Prl3b1 is associated withreduced syncytiotrophoblasts and sinusoidal trophoblast giant cells, impairsplacental labyrinth formation. Importantly, human trophoblast organoidsexposed to androgens exhibit analogous changes, showing impairedtrophoblast differentiation as a key feature in PCOS-related pregnancycomplications. These findings provide new insights into the potential cellulartargets for future treatments., CC BY 4.0E-mail: elisabet.stener-victorin@ki.se; qiaolin.deng@ki.seThe authors thank Strategic Research Program in Diabetes at the Karolinska Institutet for the use of TSE Systems and EchoMRI in the Metabolic Phenotyping Centre; and the histological Core Facility-Histocore, Biomedicum at the Karolinska Institutet. This work was supported by Swedish Medical Research Council: project no. 2022-00550 (ESV), 2020-00253 (QD); Knut and Alice Wallenberg Foundation: 2019.0211 (QD); Distinguished Investigator Grant – Endocrinology and Metabolism, Novo Nordisk Foundation: NNF22OC0072904, and project grant NNF18OC0033992 and NNF19OC0056647 (ESV); Diabetes Foundation: DIA2021-633 and DIA2022-708 (ESV); Karolinska Institutet KID funding: 2023-0005 and 2020-00990 (ESV); Karolinska Institutet faculty funded position (QD); Regional Agreement on Medical Training and Clinical Research between the Stockholm County Council and the Karolinska Institutet: 20 190 079 (ESV).