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Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome
Lund Univ, Scania Univ Hosp, Diabet Ctr, Epigenet & Diabet Unit,Dept Clin Sci, Malmö, Sweden.
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden; Univ Skövde, Sch Hlth & Educ, Skövde, Sweden.
Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden.
Karolinska Inst, Dept Physiol & Pharmacol, Stockholm, Sweden.
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2018 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 103, no 12, p. 4465-4477Article in journal (Refereed) Published
Abstract [en]

Context: Insulin resistance in skeletal muscle is a major risk factor for the development of type 2 diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying insulin resistance in PCOS are largely unknown.

Objective: To investigate the genome-wide DNA methylation and gene expression patterns in skeletal muscle from women with PCOS and controls and relate them to phenotypic variations.

Design/Participants: In a case-control study, skeletal muscle biopsies from women with PCOS (n = 17) and age-, weight-, and body mass index‒matched controls (n = 14) were analyzed by array-based DNA methylation and mRNA expression profiling.

Results: Eighty-five unique transcripts were differentially expressed in muscle from women with PCOS vs controls, including DYRK1A, SYNPO2, SCP2, and NAMPT. Furthermore, women with PCOS had reduced expression of genes involved in immune system pathways. Two CpG sites showed differential DNA methylation after correction for multiple testing. However, an mRNA expression of ∼30% of the differentially expressed genes correlated with DNA methylation levels of CpG sites in or near the gene. Functional follow-up studies demonstrated that KLF10 is under transcriptional control of insulin, where insulin promotes glycogen accumulation in myotubes of human muscle cells. Testosterone downregulates the expression levels of COL1A1 and MAP2K6.

Conclusion: PCOS is associated with aberrant skeletal muscle gene expression with dysregulated pathways. Furthermore, we identified specific changes in muscle DNA methylation that may affect gene expression. This study showed that women with PCOS have epigenetic and transcriptional changes in skeletal muscle that, in part, can explain the metabolic abnormalities seen in these women.

Place, publisher, year, edition, pages
2018. Vol. 103, no 12, p. 4465-4477
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:uu:diva-375854DOI: 10.1210/jc.2018-00935ISI: 000456138900017PubMedID: 30113663OAI: oai:DiVA.org:uu-375854DiVA, id: diva2:1284925
Funder
Swedish Society of Medicine, 2014-2775; 2016-02486Novo Nordisk, NNF17OC002672Stockholm County CouncilAvailable from: 2019-02-01 Created: 2019-02-01 Last updated: 2019-02-01Bibliographically approved

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