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Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome

Artikel i vetenskaplig tidskrift
Författare E. Nilsson
Anna Benrick
Milana Kokosar
A. Krook
E. Lindgren
T. Kallman
M. M. Martis
K. Hojlund
C. Ling
E. Stener-Victorin
Publicerad i Journal of Clinical Endocrinology & Metabolism
Volym 103
Nummer/häfte 12
Sidor 4465-4477
ISSN 0021-972X
Publiceringsår 2018
Publicerad vid Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Sidor 4465-4477
Språk en
Länkar dx.doi.org/10.1210/jc.2018-00935
Ämnesord human adipose-tissue, hla-g, glucose-metabolism, insulin-resistance, glycogen-synthase, DNA methylation, human myotubes, expression, phosphorylation, klf10, Endocrinology & Metabolism
Ämneskategorier Endokrinologi och diabetes

Sammanfattning

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 similar to 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.

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