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

J Clin Endocrinol Metab. 2018 Dec 1;103(12):4465-4477. doi: 10.1210/jc.2018-00935.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01457209.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biopsy
  • Case-Control Studies
  • Cells, Cultured
  • Collagen Type I / metabolism
  • Collagen Type I, alpha 1 Chain
  • CpG Islands / genetics
  • DNA Methylation*
  • Down-Regulation
  • Early Growth Response Transcription Factors / genetics
  • Early Growth Response Transcription Factors / metabolism
  • Epigenesis, Genetic*
  • Female
  • Follow-Up Studies
  • Gene Expression Profiling
  • Glycogen / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism
  • MAP Kinase Kinase 6 / metabolism
  • Muscle Fibers, Skeletal
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Polycystic Ovary Syndrome / complications
  • Polycystic Ovary Syndrome / genetics*
  • Polycystic Ovary Syndrome / metabolism
  • Primary Cell Culture
  • Testosterone / metabolism

Substances

  • Collagen Type I
  • Collagen Type I, alpha 1 Chain
  • Early Growth Response Transcription Factors
  • Insulin
  • KLF10 protein, human
  • Kruppel-Like Transcription Factors
  • Testosterone
  • Glycogen
  • MAP Kinase Kinase 6
  • MAP2K6 protein, human

Associated data

  • ClinicalTrials.gov/NCT01457209