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
; Vavakova, Magdalena
LU
; Ahmad Mir, Bilal
LU
; Säll, Johanna
LU
; Perfilyev, Alexander
LU
; Martin, Melina
LU
; Jansson, Per-Anders
; Davegårdh, Cajsa
LU
; Asplund, Olof
LU
and Hansson, Ola
LU
, 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.
(Less)
- author
- Ling, Charlotte
LU
; Vavakova, Magdalena
LU
; Ahmad Mir, Bilal
LU
; Säll, Johanna
LU
; Perfilyev, Alexander
LU
; Martin, Melina
LU
; Jansson, Per-Anders
; Davegårdh, Cajsa
LU
; Asplund, Olof
LU
and Hansson, Ola
LU
, et al. (More)
- Ling, Charlotte
LU
; Vavakova, Magdalena
LU
; Ahmad Mir, Bilal
LU
; Säll, Johanna
LU
; Perfilyev, Alexander
LU
; Martin, Melina
LU
; Jansson, Per-Anders
; Davegårdh, Cajsa
LU
; Asplund, Olof
LU
; Hansson, Ola
LU
; Vaag, Allan
LU
and Nilsson, Emma
LU
(Less)
- organization
-
- EpiHealth: Epidemiology for Health
- Diabetes - Epigenetics (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- Protein Phosphorylation (research group)
- Translational Muscle Research (research group)
- Genetics and Diabetes
- LU Profile Area: Proactive Ageing
- EXODIAB VAAG ALLAN
- Translational Diabetes Research (research group)
- publishing date
- 2024-12-02
- type
- Contribution to journal
- 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}},
}