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Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism

Ling, Charlotte LU orcid ; Vavakova, Magdalena LU ; Ahmad Mir, Bilal LU orcid ; Säll, Johanna LU orcid ; Perfilyev, Alexander LU orcid ; Martin, Melina LU ; Jansson, Per-Anders ; Davegårdh, Cajsa LU orcid ; Asplund, Olof LU and Hansson, Ola LU orcid , et al. (2024) In BMC Medicine 22(1).
Abstract

BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.

METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.

RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of... (More)

BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.

METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.

RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.

CONCLUSIONS: Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.

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publication status
published
subject
keywords
Humans, Muscle, Skeletal/metabolism, Diabetes Mellitus, Type 2/genetics, MicroRNAs/genetics, Twins, Monozygotic/genetics, DNA Methylation, Middle Aged, Male, RNA, Messenger/genetics, Female, Gene Expression Profiling, Aged, Insulin Resistance/genetics, Gene Expression Regulation, Adult, Multiomics
in
BMC Medicine
volume
22
issue
1
article number
572
publisher
BioMed Central (BMC)
external identifiers
  • scopus:85211099515
  • pmid:39623445
ISSN
1741-7015
DOI
10.1186/s12916-024-03789-y
language
English
LU publication?
yes
additional info
© 2024. The Author(s).
id
f238ba07-493f-40bf-a45c-0a393e22abce
date added to LUP
2025-01-07 10:22:26
date last changed
2025-06-25 18:46:09
@article{f238ba07-493f-40bf-a45c-0a393e22abce,
  abstract     = {{<p>BACKGROUND: A large proportion of skeletal muscle insulin resistance in type 2 diabetes (T2D) is caused by environmental factors.</p><p>METHODS: By applying multiomics mRNA, microRNA (miRNA), and DNA methylation platforms in biopsies from 20 monozygotic twin pairs discordant for T2D, we aimed to delineate the epigenetic and transcriptional machinery underlying non-genetic muscle insulin resistance in T2D.</p><p>RESULTS: Using gene set enrichment analysis (GSEA), we found decreased mRNA expression of genes involved in extracellular matrix organization, branched-chain amino acid catabolism, metabolism of vitamins and cofactors, lipid metabolism, muscle contraction, signaling by receptor tyrosine kinases pathways, and translocation of glucose transporter 4 (GLUT4) to the plasma membrane in muscle from twins with T2D. Differential expression levels of one or more predicted target relevant miRNA(s) were identified for approximately 35% of the dysregulated GSEA pathways. These include miRNAs with a significant overrepresentation of targets involved in GLUT4 translocation (miR-4643 and miR-548z), signaling by receptor tyrosine kinases pathways (miR-607), and muscle contraction (miR-4658). Acquired DNA methylation changes in skeletal muscle were quantitatively small in twins with T2D compared with the co-twins without T2D. Key methylation and expression results were validated in muscle, myotubes, and/or myoblasts from unrelated subjects with T2D and controls. Finally, mimicking T2D-associated changes by overexpressing miR-548 and miR-607 in cultured myotubes decreased expression of target genes, GLUT4 and FGFR4, respectively, and impaired insulin-stimulated phosphorylation of Akt (Ser473) and TBC1D4.</p><p>CONCLUSIONS: Together, we show that T2D is associated with non- and epigenetically determined differential transcriptional regulation of pathways regulating skeletal muscle metabolism and contraction.</p>}},
  author       = {{Ling, Charlotte and Vavakova, Magdalena and Ahmad Mir, Bilal and Säll, Johanna and Perfilyev, Alexander and Martin, Melina and Jansson, Per-Anders and Davegårdh, Cajsa and Asplund, Olof and Hansson, Ola and Vaag, Allan and Nilsson, Emma}},
  issn         = {{1741-7015}},
  keywords     = {{Humans; Muscle, Skeletal/metabolism; Diabetes Mellitus, Type 2/genetics; MicroRNAs/genetics; Twins, Monozygotic/genetics; DNA Methylation; Middle Aged; Male; RNA, Messenger/genetics; Female; Gene Expression Profiling; Aged; Insulin Resistance/genetics; Gene Expression Regulation; Adult; Multiomics}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Medicine}},
  title        = {{Multiomics profiling of DNA methylation, microRNA, and mRNA in skeletal muscle from monozygotic twin pairs discordant for type 2 diabetes identifies dysregulated genes controlling metabolism}},
  url          = {{http://dx.doi.org/10.1186/s12916-024-03789-y}},
  doi          = {{10.1186/s12916-024-03789-y}},
  volume       = {{22}},
  year         = {{2024}},
}