Skeletal muscle bioenergetics, lipid metabolism and androgen excess in polycystic ovary syndrome: evidence from molecular and human in vivo studies

Leanne Cussen; Tara McDonnell; Clare Miller; Zarah Farahbakhsh; Ger Cageny; Ludovica Di Martino; Triona Ni Chonghaile; Brenton Cavanagh; Wiebke Arlt; Mark Sherlock; Jeremy Tomlinson; Leanne Hodson; Marie McIlroy; Michael O

doi:10.1530/endoabs.115.OC7

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Endocrine Abstracts (2026) 115 OC7 | DOI: 10.1530/endoabs.115.OC7

IES2025 Oral Communications Oral Communications (14 abstracts)

Skeletal muscle bioenergetics, lipid metabolism and androgen excess in polycystic ovary syndrome: evidence from molecular and human in vivo studies

Leanne Cussen ^1,2 , Tara McDonnell ^1,2 , Clare Miller ^1,2 , Zarah Farahbakhsh ¹ , Ger Cageny ³ , Ludovica Di Martino ¹ , Triona Ni Chonghaile ¹ , Brenton Cavanagh ¹ , Wiebke Arlt ⁴ , Mark Sherlock ^1,2 , Jeremy Tomlinson ⁵ , Leanne Hodson ⁵ , Marie McIlroy ^1* & Michael O’Reilly ^1,2*

Author affiliations

¹Royal College of Surgeons, Dublin, Ireland; ²Beaumont Hospital, Dublin, Ireland; ³University College Dublin, Dublin, Ireland; ⁴London Institute of Medical Science, London, UK; ⁵University of Oxford, Oxford, UK *Joint senior authors

Polycystic ovary syndrome (PCOS) is characterised by androgen excess and insulin resistance. Skeletal muscle (SkM) mitochondrial dysfunction and altered lipid biology are cardinal features in other insulin resistance disorders; however, their role in PCOS is incompletely characterised. We hypothesised that androgen excess is a central driver of SkM mitochondrial dysfunction in PCOS. Integrated in-vitro, ex-vivo, and in-vivo approaches examined SkM mitochondrial function and lipid handling. Primary myotubes from women with PCOS (n = 3) and controls (n = 1) underwent high-content live-cell imaging and Seahorse XF extracellular flux analysis. Ex vivo proteomics and super-resolution microscopy were performed on muscle biopsies. Women with PCOS (n = 10) underwent a mixed meal test in vivo before and after 28 days of oral bicalutamide. In vitro, androstenedione induced lipid droplet accumulation and altered mitochondrial membrane potential in PCOS myotubes. Baseline bioenergetic profiling revealed reductions in basal (-18 %), maximal (-37%) and spare respiratory capacity (-48%) in PCOS myotubes (P < 0.001 for each) compared to controls. Fuel-flexibility testing demonstrated impaired adaptability in PCOS compared to controls. Proteomic analysis revealed downregulation of oxidative phosphorylation proteins and upregulation of glycolytic enzymes in PCOS SkM compared to controls. In vivo, Bicalutamide exposure for 28 days induced significant changes in AUC across a mixed meal test in NEFAs, lactate, glycerol and glucose (P < 0.05 for each). These findings suggest that PCOS is associated with altered mitochondrial function, lipid handling and metabolic flexibility at muscle and systemic levels. Modulation of androgen exposure at systemic or tissue-specific level offers therapeutic promise for treatment of PCOS-related metabolic disease.