@article{77b847c99955483a8d570944e538d8f9,
title = "Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle",
abstract = "Background: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans. Methods: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18–89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html). Results: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate. Conclusions: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).",
keywords = "Ageing, DNA methylation, Epigenetic clock, Epigenetics, Meta-analysis, Omics, Skeletal muscle",
author = "Sarah Voisin and Macsue Jacques and Shanie Landen and Harvey, \{Nicholas R.\} and Haupt, \{Larisa M.\} and Griffiths, \{Lyn R.\} and Sofiya Gancheva and Meriem Ouni and Markus J{\"a}hnert and Ashton, \{Kevin J.\} and Coffey, \{Vernon G.\} and Thompson, \{Jamie Lee M.\} and Doering, \{Thomas M.\} and Anne Gabory and Claudine Junien and Robert Caiazzo and H{\'e}l{\`e}ne Verkindt and Violetta Raverdy and Fran{\c c}ois Pattou and Philippe Froguel and Craig, \{Jeffrey M.\} and Sara Blocquiaux and Martine Thomis and Sharples, \{Adam P.\} and Annette Sch{\"u}rmann and Michael Roden and Steve Horvath and Nir Eynon",
note = "Funding Information: We are grateful for the support of the Australian National Health and Medical Research Council (NHMRC) via S.V.'s Early Career Research Fellowship (APP11577321) and N.E.'s Career Development Fellowship (APP1140644). We are also grateful for the support of the Jack Brockoff Foundation via S.V.'s medical grant. We also thank the Australian Research Council (ARC) for supporting this study (DP190103081 and DP200101830). The Gene SMART and LITER studies were both supported by the Collaborative Research Network for Advancing Exercise and Sports Science (201202) from the Department of Education and Training, Australia. N.R.H. and Ms J.‐L.M.T. were supported by a PhD stipend also provided by Bond University CRN‐AESS. This research was also supported by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia—Queensland Node project (L.R.G.). A.P.S. was supported by GlaxoSmithKline, North Staffordshire Medical Institute, the Society fort Endocrinology, the Medical Research Council (MRC) and Engineering and Physical Sciences Research Council (EPSRC), UK Doctoral Training Centre, and the Norwegian School of Sport Sciences (Norges Idrettsh{\o}gskole). The work was also supported by the German Federal Ministry of Education and Research [Bundesministerium f{\"u}r Bildung und Forschung (BMBF): DZD Grant 82DZD00302] and the Brandenburg State (Germany). The EPIK study was supported by the Foundation Scientific Research—Flanders (FWO Grant F.0898.15). Funding Information: We are grateful for the support of the Australian National Health and Medical Research Council (NHMRC) via S.V.'s Early Career Research Fellowship (APP11577321) and N.E.'s Career Development Fellowship (APP1140644). We are also grateful for the support of the Jack Brockoff Foundation via S.V.'s medical grant. We also thank the Australian Research Council (ARC) for supporting this study (DP190103081 and DP200101830). The Gene SMART and LITER studies were both supported by the Collaborative Research Network for Advancing Exercise and Sports Science (201202) from the Department of Education and Training, Australia. N.R.H. and Ms J.-L.M.T. were supported by a PhD stipend also provided by Bond University CRN-AESS. This research was also supported by infrastructure purchased with Australian Government EIF Super Science Funds as part of the Therapeutic Innovation Australia—Queensland Node project (L.R.G.). A.P.S. was supported by GlaxoSmithKline, North Staffordshire Medical Institute, the Society fort Endocrinology, the Medical Research Council (MRC) and Engineering and Physical Sciences Research Council (EPSRC), UK Doctoral Training Centre, and the Norwegian School of Sport Sciences (Norges Idrettsh{\o}gskole). The work was also supported by the German Federal Ministry of Education and Research [Bundesministerium f{\"u}r Bildung und Forschung (BMBF): DZD Grant 82DZD00302] and the Brandenburg State (Germany). The EPIK study was supported by the Foundation Scientific Research—Flanders (FWO Grant F.0898.15). We would like to thank Dr Mark Ziemann from Deakin University for his critical feedback on the manuscript. We also greatly acknowledge Erika Guzman at the ATGC/IHBI/QUT for performing the HMEPIC assays in the LITER study. The authors of this manuscript certify that they comply with the ethical guidelines for authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle.64 Publisher Copyright: {\textcopyright} 2021 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley \& Sons Ltd on behalf of Society on Sarcopenia, Cachexia and Wasting Disorders.",
year = "2021",
month = aug,
doi = "10.1002/jcsm.12741",
language = "English",
volume = "12",
pages = "1064--1078",
journal = "Journal of Cachexia, Sarcopenia and Muscle",
issn = "2190-5991",
publisher = "Wiley-VCH Verlag GmbH \& Co. KGaA",
number = "4",
}