| Autor: |
Turner DC; Institute for Physical Performance, Norwegian School of Sport Sciences (NiH), Oslo, Norway.; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.; Institute for Science and Technology in Medicine (ISTM), School of Pharmacy & Bioengineering, Keele University, Staffordshire, UK., Gorski PP; Institute for Physical Performance, Norwegian School of Sport Sciences (NiH), Oslo, Norway.; Institute for Science and Technology in Medicine (ISTM), School of Pharmacy & Bioengineering, Keele University, Staffordshire, UK., Maasar MF; Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK., Seaborne RA; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.; Institute for Science and Technology in Medicine (ISTM), School of Pharmacy & Bioengineering, Keele University, Staffordshire, UK.; Centre for Genomics and Child Health, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK., Baumert P; Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.; Exercise Biology Group, Faculty of Sport and Health Sciences, Technical University of Munich, Munich, Germany., Brown AD; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK., Kitchen MO; Institute for Science and Technology in Medicine (ISTM), School of Pharmacy & Bioengineering, Keele University, Staffordshire, UK., Erskine RM; Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.; Institute of Sport, Exercise and Health, University College London, London, UK., Dos-Remedios I; Orthopedics Department, University Hospitals of the North Midlands, Keele University, Staffordshire, UK., Voisin S; Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia., Eynon N; Institute for Health and Sport (iHeS), Victoria University, Footscray, VIC, Australia., Sultanov RI; Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Borisov OV; Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Bonn, Germany., Larin AK; Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Semenova EA; Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Popov DV; Laboratory of Exercise Physiology, Institute of Biomedical Problems of the Russian Academy of Sciences, Moscow, Russia., Generozov EV; Department of Molecular Biology and Genetics, Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Stewart CE; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK., Drust B; School of Sport, Exercise and Rehabilitation Sciences, College of Life and Environmental Sciences, University of Birmingham, Birmingham, UK., Owens DJ; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.; Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK., Ahmetov II; Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK. I.Ahmetov@ljmu.ac.uk.; Laboratory of Molecular Genetics, Kazan State Medical University, Kazan, Russia. I.Ahmetov@ljmu.ac.uk.; Department of Physical Education, Plekhanov Russian University of Economics, Moscow, Russia. I.Ahmetov@ljmu.ac.uk., Sharples AP; Institute for Physical Performance, Norwegian School of Sport Sciences (NiH), Oslo, Norway. a.p.sharples@googlemail.com.; Stem Cells, Ageing and Molecular Physiology Unit, Exercise Metabolism and Adaptation Research Group, Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK. a.p.sharples@googlemail.com.; Institute for Science and Technology in Medicine (ISTM), School of Pharmacy & Bioengineering, Keele University, Staffordshire, UK. a.p.sharples@googlemail.com. |
| Abstrakt: |
Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6-8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes. |
