DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults
DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults
Background: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. Methods: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. Results: Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. Conclusions: These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR.
Aged, DNA Methylation, Female, Glycated Hemoglobin, Humans, Insulin Resistance/physiology, Insulin/metabolism, Male, Myoblasts/metabolism, Signal Transduction, HOMA2-IR, Skeletal muscle, DNA methylation, Insulin resistance
Burton, Mark A.
250319ad-90dc-4651-b118-d5dbe5eaafa6
Garratt, Emma S.
51598847-7206-4945-89cb-d495e99659f3
Hewitt, Matthew O.
25b6b2d1-cb86-4ea0-83b6-8953e418afba
Sharkh, Hanan Y.
79bc72b5-421e-4cb6-9a35-03cec8dc5daf
Antoun, Elie
23e4ee54-9652-41cd-9eb0-066cfcc598c9
Westbury, Leo D.
08fbb4e9-305c-4724-bd0c-b963a5054229
Dennison, Elaine M.
ee647287-edb4-4392-8361-e59fd505b1d1
Harvey, Nicholas C.
ce487fb4-d360-4aac-9d17-9466d6cba145
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
MacIsaac, Julia L.
4e74f97f-0016-4bfd-9154-25fa22e2a4b6
Kobor, Michael S.
e387ab6f-d060-4d39-95c6-acf0c3b9687b
Patel, Harnish P
514aba46-4dc9-4011-b393-ce83c6206754
Godfrey, Keith M.
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burton, Mark A.
250319ad-90dc-4651-b118-d5dbe5eaafa6
Garratt, Emma S.
51598847-7206-4945-89cb-d495e99659f3
Hewitt, Matthew O.
25b6b2d1-cb86-4ea0-83b6-8953e418afba
Sharkh, Hanan Y.
79bc72b5-421e-4cb6-9a35-03cec8dc5daf
Antoun, Elie
23e4ee54-9652-41cd-9eb0-066cfcc598c9
Westbury, Leo D.
08fbb4e9-305c-4724-bd0c-b963a5054229
Dennison, Elaine M.
ee647287-edb4-4392-8361-e59fd505b1d1
Harvey, Nicholas C.
ce487fb4-d360-4aac-9d17-9466d6cba145
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
MacIsaac, Julia L.
4e74f97f-0016-4bfd-9154-25fa22e2a4b6
Kobor, Michael S.
e387ab6f-d060-4d39-95c6-acf0c3b9687b
Patel, Harnish P
514aba46-4dc9-4011-b393-ce83c6206754
Godfrey, Keith M.
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen A.
eeaaa78d-0c4d-4033-a178-60ce7345a2cc
Burton, Mark A., Garratt, Emma S., Hewitt, Matthew O., Sharkh, Hanan Y., Antoun, Elie, Westbury, Leo D., Dennison, Elaine M., Harvey, Nicholas C., Cooper, Cyrus, MacIsaac, Julia L., Kobor, Michael S., Patel, Harnish P, Godfrey, Keith M. and Lillycrop, Karen A.
(2023)
DNA methylation of insulin signaling pathways is associated with HOMA2-IR in primary myoblasts from older adults.
Skeletal Muscle, 13 (1), [17].
(doi:10.1186/s13395-023-00326-y).
Abstract
Background: While ageing is associated with increased insulin resistance (IR), the molecular mechanisms underlying increased IR in the muscle, the primary organ for glucose clearance, have yet to be elucidated in older individuals. As epigenetic processes are suggested to contribute to the development of ageing-associated diseases, we investigated whether differential DNA methylation was associated with IR in human primary muscle stem cells (myoblasts) from community-dwelling older individuals. Methods: We measured DNA methylation (Infinium HumanMethylationEPIC BeadChip) in myoblast cultures from vastus lateralis biopsies (119 males/females, mean age 78.24 years) from the Hertfordshire Sarcopenia Study extension (HSSe) and examined differentially methylated cytosine phosphate guanine (CpG) sites (dmCpG), regions (DMRs) and gene pathways associated with HOMA2-IR, an index for the assessment of insulin resistance, and levels of glycated hemoglobin HbA1c. Results: Thirty-eight dmCpGs (false discovery rate (FDR) < 0.05) were associated with HOMA2-IR, with dmCpGs enriched in genes linked with JNK, AMPK and insulin signaling. The methylation signal associated with HOMA2-IR was attenuated after the addition of either BMI (6 dmCpGs), appendicular lean mass index (ALMi) (7 dmCpGs), grip strength (15 dmCpGs) or gait speed (23 dmCpGs) as covariates in the model. There were 8 DMRs (Stouffer < 0.05) associated with HOMA2-IR, including DMRs within T-box transcription factor (TBX1) and nuclear receptor subfamily-2 group F member-2 (NR2F2); the DMRs within TBX1 and NR2F2 remained associated with HOMA2-IR after adjustment for BMI, ALMi, grip strength or gait speed. Forty-nine dmCpGs and 21 DMRs were associated with HbA1c, with cg13451048, located within exoribonuclease family member 3 (ERI3) associated with both HOMA2-IR and HbA1c. HOMA2-IR and HbA1c were not associated with accelerated epigenetic ageing. Conclusions: These findings suggest that insulin resistance is associated with differential DNA methylation in human primary myoblasts with both muscle mass and body composition making a significant contribution to the methylation changes associated with IR.
Text
s13395-023-00326-y
- Version of Record
More information
Accepted/In Press date: 9 October 2023
e-pub ahead of print date: 28 October 2023
Additional Information:
Funding Information:
This work was supported by grant funding from the Medical Research Council (MC_U47585827, MC_ST_U2055, MC_PC_21003; MC_PC_21001), Benevolent AI Limited, Arthritis Research UK, Royal Osteoporosis Society, International Osteoporosis Foundation, Cohen Trust, NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, NIHR Musculoskeletal Biomedical Research Unit, and University of Oxford. K.M.G. is supported by the UK Medical Research Council (MC_UU_20/4), the US National Institute On Aging of the National Institutes of Health (award number U24AG047867), the UK Economic and Social Research Council and the Biotechnology and Biological Sciences Research Council (award number ES/M0099X/), the National Institute for Health Research (as an NIHR Senior Investigator (NF-SI-055–0042) and through the NIHR Southampton Biomedical Research Centre, and the European Union’s Erasmus + Capacity-Building ImpENSA Project. H.P.P. is supported by the National Institute for Health Research through the NIHR Southampton Biomedical Research Centre. This report is independent research, and the views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The grant funders had no role in the design, collection, analysis and interpretation of the data, writing of the paper or decision to submit for publication. For the purpose of Open Access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2023, The Author(s).
Keywords:
Aged, DNA Methylation, Female, Glycated Hemoglobin, Humans, Insulin Resistance/physiology, Insulin/metabolism, Male, Myoblasts/metabolism, Signal Transduction, HOMA2-IR, Skeletal muscle, DNA methylation, Insulin resistance
Identifiers
Local EPrints ID: 483431
URI: http://eprints.soton.ac.uk/id/eprint/483431
ISSN: 2044-5040
PURE UUID: 7e08b5be-ecda-4d89-9dc6-99055d14d28a
Catalogue record
Date deposited: 30 Oct 2023 18:03
Last modified: 14 Aug 2024 01:52
Export record
Altmetrics
Contributors
Author:
Emma S. Garratt
Author:
Matthew O. Hewitt
Author:
Elie Antoun
Author:
Leo D. Westbury
Author:
Julia L. MacIsaac
Author:
Michael S. Kobor
Author:
Harnish P Patel
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics
