Genome-wide DNA methylation changes with age in disease-free human skeletal muscle

Buck Institute for Research on Aging, 8001 Redwood Blvd, Novato, CA, 94945, USA.
Aging cell (Impact Factor: 6.34). 11/2013; 13(2). DOI: 10.1111/acel.12180
Source: PubMed


A decline in skeletal muscle mass and function with aging is well recognized, but remains poorly characterized at the molecular level. Here we report for the first time a genome-wide study of DNA methylation dynamics in skeletal muscle of healthy male individuals during normal human aging. We predominantly observed hypermethylation throughout the genome within the aged group as compared to the young subjects. Differentially methylated CpG (dmCpG) nucleotides tend to arise intragenically, and are underrepresented in promoters and are overrepresented in the middle and 3' end of genes. The intragenic methylation changes are over represented in genes that guide the formation of the junction of the motor neuron and myofibers. We report a low level of correlation of gene expression from previous studies of aged muscle with our current analysis of DNA methylation status. For those genes that had both changes in methylation and gene expression with age, we observed a reverse correlation, with the exception of intragenic hypermethylated genes, that were correlated with increased gene expression. We suggest that a minimal number of dmCpG sites or select sites are required to be altered in order to correlate with gene expression changes. Finally, we identified 500 dmCpG sites that perform well in discriminating young from old samples. Our findings highlight epigenetic links between aging post-mitotic skeletal muscle and DNA methylation. This article is protected by copyright. All rights reserved.

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Available from: Alan E Hubbard, Sep 15, 2014
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    • "To this point, Russ and Lanza in 2011 highlighted many known factors that contribute to the observed reductions in skeletal muscle performance with aging including alterations in several pathways of ATP production including glycolytic components, oxidative phosphorylation , and the supply and demand of numerous metabolic factors throughout muscular contractions (Russ and Lanza 2011). Recently, Zykovich reported on genome-wide changes in DNA methylation status across the age spectrum in healthy human skeletal muscle (Zykovich et al. 2014). Other factors such as physical activity status (Davis et al. 1998; Paterson et al. 2007), contraction type (Avin and Law 2011; Callahan et al. 2009) and metabolic (Schlenska and Kleine 1980) as well as antioxidant (Marzani et al. 2005) enzymatic changes have also been introduced as other factors that impact skeletal muscle health and how it performs. "
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    ABSTRACT: To examine age-related differences in intramuscular concentrations of adenosine triphosphate (ATP), free creatine (FCr), phosphocreatine (PCr) and total creatine (TCr) and if these differences were related to muscle performance. Forty-two healthy, non-sedentary, males between 20 and 76 years provided muscle samples to determine [ATP], [FCr], [PCr], and [TCr]. Maximal strength and endurance were assessed and correlated with intramuscular variables. Intramuscular [ATP] decreased by 13.5 % (p = 0.013) in the older cohort (18.0 ± 0.6 mmol/kg dry wt) vs. the young cohort (20.8 ± 0.9 mmol/kg dry wt) and was significantly correlated to age (r = -0.38, p = 0.008). No other differences were observed between age groups for intramuscular [PCr], [FCr], [TCr], or [PCr]:[TCr] (p > 0.05). The older cohort consumed significantly less (p < 0.05) dietary protein when compared to the young cohort. Bivariate correlations were found for intramuscular [ATP] and lower body 1RM (r = 0.24, p = 0.066), leg press volume and free creatine (r = 0.325, p = 0.036) and leg press repetitions and free creatine (r = 0.373, p = 0.015). Partial correlations controlling for age eliminated the relationship between [ATP] and 1RM while intramuscular free creatine and leg press repetitions remained significant (p < 0.05) and leg press volume approached significance (p = 0.095). These results expand upon previous observations indicative of age-related reductions in intramuscular [ATP] and dietary protein intake. The lack of change in other intramuscular PCr system markers are suggestive of dysfunctions at the mitochondrial level while the impact of neuromuscular changes, lean mass cross-sectional area and differences in physical activity are also important.
    Arbeitsphysiologie 08/2015; DOI:10.1007/s00421-015-3246-1 · 2.19 Impact Factor
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    • "The score of the methylation value associated with each CpG site was defined as the beta value multiplied by 1000, with the beta value in turn defined as the proportion of the intensity value from the methylated bead type from the sum of the intensity values from both methylated and unmethylated bead type plus 100. Published methylation data of primary cells from tissues of brain (Day et al., 2013; Kozlenkov et al., 2014; Wockner et al., 2014), muscle (Ribel-Madsen et al., 2012; Day et al., 2013; Zykovich et al., 2013), fat (Ribel-Madsen et al., 2012; Grundberg et al., 2013), and saliva (Liu et al., 2010; Bocklandt et al., 2011; Souren et al., 2013; Park et al., 2014) were obtained through Gene Expression Omnibus (GEO) (http:// (Edgar et al., 2002) and ArrayExpress ( (Rustici et al., 2012). "
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    ABSTRACT: Although apolipoprotein E (APOE) variants are associated with age-related diseases, the underlying mechanism is unknown and DNA methylation may be a potential one. With methylation data, measured by the Infinium Human Methylation 450 array, from 993 participants (age ranging from 18 to 87 years) in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study, and from Encyclopedia of DNA Elements (ENCODE) consortium, combined with published methylation datasets, we described the methylation pattern of 13 CpG sites within APOE locus, their correlations with gene expression across cell types, and their relationships with age, plasma lipids, and sequence variants. Based on methylation levels and the genetic regions, we categorized the 13 APOE CpG sites into three groups: Group 1 showed hypermethylation (> 50%) and were located in the promoter region, Group 2 exhibited hypomethylation (< 50%) and were located in the first two exons and introns, and Group 3 showed hypermethylation (> 50%) and were located in the exon 4. APOE methylation was negatively correlated with gene expression (minimum r = -0.66, P = 0.004). APOE methylation was significantly associated with age (minimum P = 2.06E-08) and plasma total cholesterol (minimum P = 3.53E-03). Finally, APOE methylation patterns differed across APOE ε variants (minimum P = 3.51E-05) and the promoter variant rs405509 (minimum P = 0.01), which further showed a significant interaction with age (P = 0.03). These findings suggest that methylation may be a potential mechanistic explanation for APOE functions related to aging and call for further molecular mechanistic studies. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
    Aging cell 12/2014; 14(1). DOI:10.1111/acel.12293 · 6.34 Impact Factor
    • "Age-associated hypermethylation is enriched in CpG islands (CGIs) and shore regions ( Johansson et al., 2013 ; McClay et al., 2014 ), whereas hypomethylation occurs rather outside of CGIs ( Christensen et al., 2009 ) and in repetitive Alu elements ( Gentilini et al., 2013 ). The majority of age-related DNAm changes are outside of promoter regions but enriched in enhancer binding sites ( Johansson et al., 2013 ), intragenic regions, and 3 ′ -ends of genes ( Zykovich et al., 2014 ). Furthermore , they are enriched in developmental genes and are not accompanied by gene expression changes ( Steegenga et al., 2014 ). "
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    ABSTRACT: Abstract Aging is associated with the deterioration of biological functions, which is either caused by accumulation of random defects or mediated by a controlled process. This article provides an overview of age-associated epigenetic alterations in the histone code, DNA-methylation (DNAm) pattern, and chromatin structure. In particular, age-related DNAm changes are highly reproducible at specific sites in the genome. The DNAm level at few CpGs facilitates estimation of chronological age and there is evidence that such predictions are indicative for biological age. Overall, aging appears to be associated with a tightly regulated epigenetic process, but the underlying mechanism remains to be elucidated.
    Biological Chemistry 09/2014; 395(11). DOI:10.1515/hsz-2014-0180 · 3.27 Impact Factor
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