Non-cell autonomous mechanisms control mitochondrial gene dysregulation in polycystic ovary syndrome.

Alba Moreno-Asso,Luke C Mcilvenna,Romain Barrès,Nigel K Stepto,Ali Altıntaş,Raymond J Rodgers,Javier Botella,Andrew J Mcainch,Rhiannon K Patten

doi:10.1530/jme-21-0212

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with insulin resistance and impaired energy metabolism in skeletal muscle, the aetiology of which is currently unclear. Here, we mapped the gene expression profile of skeletal muscle from women with PCOS and determined if cultured primary myotubes retain the gene expression signature of PCOS in vivo. Transcriptomic analysis of vastus lateralis biopsies collected from PCOS women showed lower expression of genes associated with mitochondrial function, while the expression of genes associated with the extracellular matrix was higher compared to controls. Altered skeletal muscle mRNA expression of mitochondrial-associated genes in PCOS was associated with lower protein expression of mitochondrial complex II–V, but not complex I, with no difference in mitochondrial DNA content. Transcriptomic analysis of primary myotube cultures established from biopsies did not display any differentially expressed genes between controls and PCOS. Comparison of gene expression profiles in skeletal muscle biopsies and primary myotube cultures showed lower expression of mitochondrial and energy metabolism-related genes in vitro, irrespective of the group. Together, our results show that the altered mitochondrial-associated gene expression in skeletal muscle in PCOS is not preserved in cultured myotubes, indicating that the in vivo extracellular milieu, rather than genetic or epigenetic factors, may drive this alteration. Dysregulation of mitochondrial-associated genes in skeletal muscle by extracellular factors may contribute to the impaired energy metabolism associated with PCOS.

Highlights

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, affecting their metabolic, reproductive and mental health (Ehrmann 2005, Teede et al 2010)
We found that mitochondrial-associated gene pathways represent the main gene expression difference in skeletal muscle of insulin-resistant women with PCOS compared to healthy controls
We show that alteration of mitochondria-related genes is lost in primary muscle cell cultures, indicating that extracellular factors present in the in vivo milieu may be responsible for the gene expression reprogramming of mitochondrial function associated genes in PCOS

Summary

Introduction

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-aged women, affecting their metabolic, reproductive and mental health (Ehrmann 2005, Teede et al 2010). PCOS has a strong metabolic component with insulin resistance being present in 38–95% of women with PCOS (Moghetti et al 2013, Stepto et al 2013, Tosi et al 2017). Insulin resistance and compensatory hyperinsulinaemia are considered primary drivers of PCOS pathophysiology, contributing to hyperandrogenism and reproductive dysfunction (Dunaif et al 1989, Teede et al 2010). Insulin resistance in PCOS has been suggested to be mechanistically distinct from that of other metabolic disorders (Dunaif et al 1989, Corbould 2008). There is a lack of understanding about the molecular mechanisms leading to insulin resistance in metabolic tissues (Stepto et al 2019)

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