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

Nilsson, Emma LU orcid ; Benrick, Anna ; Kokosar, Milana ; Krook, Anna ; Lindgren, Eva ; Källman, Thomas ; Martis, Mihaela M ; Højlund, Kurt ; Ling, Charlotte LU orcid and Stener-victorin, Elisabet (2018) In The Journal of clinical endocrinology and metabolism 103(12). p.4465-4477
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of clinical endocrinology and metabolism
volume
103
issue
12
pages
13 pages
publisher
Oxford University Press
external identifiers
  • scopus:85052910075
ISSN
1945-7197
DOI
10.1210/jc.2018-00935
language
English
LU publication?
yes
id
094ad7c4-0407-4555-9470-71f4d239228b
date added to LUP
2022-01-31 14:07:58
date last changed
2024-02-20 20:41:04
@article{094ad7c4-0407-4555-9470-71f4d239228b,
  abstract     = {{Context: Insulin resistance in skeletal muscle is a major risk factor for the development of type 2<br/>diabetes in women with polycystic ovary syndrome (PCOS). Despite this, the mechanisms underlying<br/>insulin resistance in PCOS are largely unknown.<br/>Objective: To investigate the genome-wide DNA methylation and gene expression patterns in<br/>skeletal muscle from women with PCOS and controls and relate them to phenotypic variations.<br/>Design/Participants: In a case-control study, skeletal muscle biopsies from women with PCOS (n =<br/>17) and age-, weight-, and body mass index‒matched controls (n = 14) were analyzed by array-based<br/>DNA methylation and mRNA expression profiling.<br/>Results: Eighty-five unique transcripts were differentially expressed in muscle from women with PCOS<br/>vs controls, including DYRK1A, SYNPO2, SCP2, and NAMPT. Furthermore, women with PCOS had<br/>reduced expression of genes involved in immune system pathways. Two CpG sites showed differential<br/>DNA methylation after correction for multiple testing. However, an mRNA expression of ;30% of the<br/>differentially expressed genes correlated with DNA methylation levels of CpG sites in or near the gene.<br/>Functional follow-up studies demonstrated that KLF10 is under transcriptional control of insulin,<br/>where insulin promotes glycogen accumulation in myotubes of human muscle cells. Testosterone<br/>downregulates the expression levels of COL1A1 and MAP2K6.<br/>Conclusion: PCOS is associated with aberrant skeletal muscle gene expression with dysregulated<br/>pathways. Furthermore, we identified specific changes in muscle DNA methylation that may affect<br/>gene expression. This study showed that women with PCOS have epigenetic and transcriptional<br/>changes in skeletal muscle that, in part, can explain the metabolic abnormalities seen in<br/>these women.}},
  author       = {{Nilsson, Emma and Benrick, Anna and Kokosar, Milana and Krook, Anna and Lindgren, Eva and Källman, Thomas and Martis, Mihaela M and Højlund, Kurt and Ling, Charlotte and Stener-victorin, Elisabet}},
  issn         = {{1945-7197}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{12}},
  pages        = {{4465--4477}},
  publisher    = {{Oxford University Press}},
  series       = {{The Journal of clinical endocrinology and metabolism}},
  title        = {{Transcriptional and Epigenetic Changes Influencing Skeletal Muscle Metabolism in Women With Polycystic Ovary Syndrome}},
  url          = {{http://dx.doi.org/10.1210/jc.2018-00935}},
  doi          = {{10.1210/jc.2018-00935}},
  volume       = {{103}},
  year         = {{2018}},
}