ORCID Profile
0000-0001-7982-9070
Current Organisation
UCSF Medical Center
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Publisher: Springer Science and Business Media LLC
Date: 21-09-2020
DOI: 10.1038/S41598-020-72730-Z
Abstract: 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.
Publisher: Cold Spring Harbor Laboratory
Date: 11-07-2023
DOI: 10.1101/2023.07.11.548561
Abstract: To identify the effects of leucine, β-hydroxy β-methylbutyrate (HMB) and branched chain amino acid (BCAA) on post-exercise cytokine responses in females and males. Males (n=53) and females (n=37) completed 100 drop jumps and consumed either no supplement, leucine (3g/d), HMB (3g/d) or BCAA (4.5g/d) from 1d pre to 14d post-exercise. Muscle soreness, squat jumps, chair rises and creatine kinase (CK) were measured at pre, post, 24h, 48h, 7 and 14d. Blood lactate (pre, post), 10 cytokines (pre, 24h, 48h, 7d) and oestradiol (pre, 7d) were also measured. Without supplementation post-exercise, soreness was induced in both males (6-fold) and females (5-fold). With supplementation, there were no increases in CK or oestradiol in females and no impact on muscle soreness, performance, or function in both sexes. In males, CK was elevated in untreated (48%) and leucine (69%) conditions vs baseline, but these were suppressed with HMB and BCAA. IL-7 was elevated in females vs males at baseline (6.3-fold), leucine increased IL-7 concentrations in females at 24h (17.0-fold), 48h (5.1-fold) vs males. With HMB, TNFr1-α increased in females at 24h (2.2-fold), 48h (2.3-fold) and 7d (2.3-fold) vs males. In males with BCAA, TNFr1-α decreased (P=0.06) from pre to 24h (6.8-fold), then increased (P .05) from 24 to 48h (8.0-fold). Although supplements were without effect on soreness following exercise, the cytokine response was evoked by exercise and impacted significantly by leucine, HMB and BCAA in females vs males. This improved cytokine response in females could lead to improved resistance to damage.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Alex Brown.