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Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS)

Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS)
Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS)
Background: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed.

Methods: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96.

Results: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis.

Conclusions: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.
DNA methylation, EZH2, Myoblasts, Sarcopenia
2190-5991
240 - 253
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Garratt, Emma
66ddd4cb-19a2-4d08-889b-12f418e6878b
Taddei, Andrea
cd9ef403-5dd8-4970-9d00-ff528ef5bd2d
Burton, Mark
250319ad-90dc-4651-b118-d5dbe5eaafa6
Barton, Sheila
4f674382-ca0b-44ad-9670-e71a0b134ef0
Titcombe, Philip
c6ecfcd6-51df-4c0d-afbe-a1ee991b7931
Westbury, Leo
5ed45df3-3df7-4bf9-bbad-07b63cd4b281
Baczynska, Alicia
03079463-27a7-4c58-84c6-0d141585af76
Migliavacca, Eugenia
eda5ed6b-ec9d-4f00-9308-6fa2cfbad9d2
Feige, Jerome N.
ed6ba764-f562-4314-b823-c6aff0d7fa47
Syddall, Holly Emma
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Dennison, Elaine
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Dodds, Richard
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Roberts, Helen
5ea688b1-ef7a-4173-9da0-26290e18f253
Richardson, Peter
40a7cc0a-39a5-413b-a163-6af017ec4093
Sayer, Avan A.
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Shaw, Sarah
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Cooper, Cyrus
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Holbrook, Joanna D.
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Patel, Harnish
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Godfrey, Keith
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Lillycrop, Karen
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Epigen Global Research Consortium
Antoun, Elie
10fc5678-b33c-4410-977d-b11234031791
Garratt, Emma
66ddd4cb-19a2-4d08-889b-12f418e6878b
Taddei, Andrea
cd9ef403-5dd8-4970-9d00-ff528ef5bd2d
Burton, Mark
250319ad-90dc-4651-b118-d5dbe5eaafa6
Barton, Sheila
4f674382-ca0b-44ad-9670-e71a0b134ef0
Titcombe, Philip
c6ecfcd6-51df-4c0d-afbe-a1ee991b7931
Westbury, Leo
5ed45df3-3df7-4bf9-bbad-07b63cd4b281
Baczynska, Alicia
03079463-27a7-4c58-84c6-0d141585af76
Migliavacca, Eugenia
eda5ed6b-ec9d-4f00-9308-6fa2cfbad9d2
Feige, Jerome N.
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Syddall, Holly Emma
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Dennison, Elaine
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Dodds, Richard
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Roberts, Helen
5ea688b1-ef7a-4173-9da0-26290e18f253
Richardson, Peter
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Sayer, Avan A.
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Shaw, Sarah
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Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Holbrook, Joanna D.
9188a129-7683-4e86-92bc-5dc2d41ac91b
Patel, Harnish
e1c0826f-d14e-49f3-8049-5b945d185523
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen
eeaaa78d-0c4d-4033-a178-60ce7345a2cc

Antoun, Elie, Garratt, Emma, Taddei, Andrea, Burton, Mark, Barton, Sheila, Titcombe, Philip, Syddall, Holly Emma, Dennison, Elaine, Sayer, Avan A., Shaw, Sarah, Cooper, Cyrus, Holbrook, Joanna D., Patel, Harnish, Godfrey, Keith and Lillycrop, Karen , Epigen Global Research Consortium (2021) Epigenome-wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS). Journal of Cachexia, Sarcopenia and Muscle, 13 (1), 240 - 253. (doi:10.1002/jcsm.12876).

Record type: Article

Abstract

Background: Sarcopenia is the age-related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed.

Methods: Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia-associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96.

Results: Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia-associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E-03), oxidative phosphorylation (P = 2.78E-02), and voltage-gated calcium channels (P = 1.59E-04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E-35), sarcopenia and gait speed (P = 4.78E-03), and sarcopenia and grip strength (P = 7.55E-06). There was also an over-representation of the sarcopenia, ALMi, grip strength, and gait speed-associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis.

Conclusions: These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

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More information

Accepted/In Press date: 29 October 2021
e-pub ahead of print date: 4 December 2021
Keywords: DNA methylation, EZH2, Myoblasts, Sarcopenia

Identifiers

Local EPrints ID: 452877
URI: http://eprints.soton.ac.uk/id/eprint/452877
ISSN: 2190-5991
PURE UUID: bba6d83e-7854-41b9-95de-ae7509b86fee
ORCID for Emma Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Leo Westbury: ORCID iD orcid.org/0009-0008-5853-8096
ORCID for Holly Emma Syddall: ORCID iD orcid.org/0000-0003-0171-0306
ORCID for Elaine Dennison: ORCID iD orcid.org/0000-0002-3048-4961
ORCID for Helen Roberts: ORCID iD orcid.org/0000-0002-5291-1880
ORCID for Sarah Shaw: ORCID iD orcid.org/0000-0002-2206-6858
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Harnish Patel: ORCID iD orcid.org/0000-0002-0081-1802
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

Catalogue record

Date deposited: 06 Jan 2022 17:38
Last modified: 18 Mar 2024 03:28

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Contributors

Author: Elie Antoun
Author: Emma Garratt ORCID iD
Author: Andrea Taddei
Author: Mark Burton
Author: Sheila Barton ORCID iD
Author: Philip Titcombe
Author: Leo Westbury ORCID iD
Author: Alicia Baczynska
Author: Eugenia Migliavacca
Author: Jerome N. Feige
Author: Elaine Dennison ORCID iD
Author: Richard Dodds
Author: Helen Roberts ORCID iD
Author: Peter Richardson
Author: Avan A. Sayer
Author: Sarah Shaw ORCID iD
Author: Cyrus Cooper ORCID iD
Author: Joanna D. Holbrook
Author: Harnish Patel ORCID iD
Author: Keith Godfrey ORCID iD
Author: Karen Lillycrop ORCID iD
Corporate Author: Epigen Global Research Consortium

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