The prevalence of sarcopenia depends on the definition used. There are, however, consistent sarcopenic characteristics, including a low muscle mass and muscle strength. Few studies have investigated the relationship between sarcopenia and genotype. A cross-sectional study was conducted with 307 community-dwelling ≥60-year-old women in South Cheshire, UK. Handgrip strength was assessed with a handgrip dynamometer and skeletal muscle mass was estimated using bioelectrical impedance. DNA was extracted from saliva (∼38%) or blood (∼62%) and 24 single-nucleotide polymorphisms (SNPs) were genotyped. Three established sarcopenia definitions -%Skeletal Muscle Mass (%SMM), Skeletal Muscle Mass Index (SMI) and European Working Group on Sarcopenia in Older People (EWGSOP) -were used to assess sarcopenia prevalence. Binary logistic regression with age as covariate was used to identify SNPs associated with sarcopenia. The prevalence of sarcopenia was: %SMM 14.7%, SMI 60.6% and EWGSOP 1.3%. Four SNPs were associated with the %SMM and SMI definitions of sarcopenia; FTO rs9939609, ESR1 rs4870044, NOS3 rs1799983 and TRHR rs7832552. The first three were associated with the %SMM definition, and TRHR rs7832552 with the SMI definition, but none were common to both sarcopenia definitions. The gene variants associated with sarcopenia may help proper counselling and interventions to prevent individuals from developing sarcopenia.Sarcopenia is defined as an ageing-related loss of both muscle mass and strength below a threshold level 1 . It is an important predictor of adverse outcomes such as limited mobility, increased risk of falls, decreased quality of life (QoL), hospitalization and mortality, and contributes to tens of millions of pounds of health care costs in the UK 1-3 . Although muscle weakness and skeletal muscle atrophy are overt characteristics of this geriatric syndrome, there is ongoing debate on the operational definition, screening and diagnosis, and optimal management and treatment of the condition 1,4-6 . The considerable heterogeneity in the reported prevalence of sarcopenia is largely attributable to the different definitions or cut-offs used 7-9 .The fact that some elderly do not show sarcopenia, whilst others of the same age do 10,11 , suggests that some individuals are more susceptible to sarcopenia than others. The different susceptibility is likely due to a combination of factors including physical activity, diet, sedentary behaviour and genetics [12][13][14][15] . Several studies have reported an association of single nucleotide polymorphisms (SNPs) with lean mass, muscle volume and muscle strength [16][17][18] . It is thus possible that individuals carrying favourable gene variants are less susceptible to sarcopenia and hence can maintain independence until later life. To date, five studies have investigated the association of SNPs with sarcopenia; limited to VDR, IL6, ACTN3 and MSTN polymorphisms [19][20][21][22][23] . The studies identified an association of ACTN3 and VDR gene variants with sarcopenia, but di...

Background Sarcopenia is characterized by progressive decreases in muscle mass, muscle strength, and muscle function with ageing. Although many studies have investigated the mechanisms of sarcopenia, its connection with epigenetic factors, such as DNA methylation, still remains poorly understood. The aim of this study was to explore sarcopenia-related DNA methylation differences in blood samples between age-matched sarcopenic and non-sarcopenic older women. Methods A sarcopenic group (n = 24) was identified and selected from a set of 247 older Caucasian women (aged 65-80 years) based on cut-off points of skeletal muscle index at 6.75 kg/m 2 and grip strength at 26 kg (the lower quintile of grip strength in the set). A non-sarcopenic group (n = 24) was created with a similar age distribution as that of the sarcopenic group. DNA methylation patterns of whole blood samples from both groups were analysed using Infinium MethylationEPIC BeadChip arrays. Differentially methylated cytosin-phosphate-guanine sites (dmCpGs) were identified at a P value threshold of 0.01 by comparing methylation levels between the sarcopenic and non-sarcopenic groups at each CpG site. dmCpG-related genes were annotated based on Homo sapiens hg19 genome build. The functions of these genes were further examined by GO and KEGG pathway enrichment analysis. Results The global methylation level of all analysed CpG sites (n = 788 074) showed no significant difference between the sarcopenic and non-sarcopenic groups (0.812), while the average methylation level of dmCpGs (n = 6258) was significantly lower in the sarcopenic group (0.004). The sarcopenic group had significantly higher methylation levels in TSS200 (the region from transcription start site to 200 nucleotides upstream of the site) and lower methylation levels in gene body and 3'UTR regions. In respect of CpG regions, CpG islands in promoters and some intragenic regions showed greater levels of methylation in the sarcopenic group. dmCpG-related KEGG pathways were mainly associated with muscle function, actin cytoskeleton regulation, and energy metabolism. Seven genes (HSPB1, PBX4, CNKSR3, ORMDL3, MIR10A, ZNF619, and CRADD) were found with the same methylation direction as previous studies of blood sample methylation during ageing. Fifty-four genes were shared with previous studies of resistance training. Conclusions Our results improve understanding of epigenetic mechanisms of sarcopenia by identifying sarcopenia-related DNA methylation differences in blood samples of older women. These methylation differences suggest underlying alterations of gene expression and pathway function, which can partially explain sarcopenia-related muscular changes.

Background Inter-individual variance in skeletal muscle is closely related to genetic architecture and epigenetic regulation. Studies have examined genetic and epigenetic relationships with characteristics of ageing muscle separately, while no study has combined both genetic and epigenetic profiles in ageing muscle research. The aim of this study was to evaluate the association between combined genetic and methylation scores and skeletal muscle phenotypes in older women. Methods Forty-eight older Caucasian women (aged 65-79 years) were included in this study. Biceps brachii thickness and vastus lateralis anatomical cross-sectional area (ACSA VL) were measured by ultrasonography. Maximum isometric elbow flexion (MVC EF) and knee extension (MVC KE) torques were measured by a customized dynamometer. The muscle-driven genetic predisposition score (GPS SNP) was calculated based on seven muscle-related single nucleotide polymorphisms (SNPs). DNA methylation levels of whole blood samples were analysed using Infinium MethylationEPIC BeadChip arrays. The DNA methylation score was calculated as a weighted sum of methylation levels of sarcopenia-driven CpG sites (MS SAR) or an overall gene-wise methylation score (MS SNP , the mean methylation level of CpG sites located in muscle-related genes). Linear regression models were built to study genetic and epigenetic associations with muscle size and strength. Three models were built with both genetic and methylation scores: (1) MS SAR + GPS SNP , (2) MS SNP + GPS SNP , and (3) gene-wise combined scores which were calculated as the ratio of the SNP score to the mean methylation level of promoters in the corresponding gene. Additional models with only a genetic or methylation score were also built. All models were adjusted for age and BMI. Results MS SAR was negatively associated with ACSA VL , MVC EF , and MVC KE and explained 10.1%, 35.5%, and 40.1% of the variance, respectively. MS SAR explained more variance in these muscular phenotypes than GPS SNP , MS SNP , and models including both genetic and methylation scores. MS SNP and GPS SNP accounted for less than 8% and 5% of the variance in all muscular phenotypes, respectively. The genotype and methylation level of CNTF was positively related to MVC KE (P = 0.03) and explained 12.2% of the variance. The adjusted R 2 and Akaike information criterion showed that models with only a MS SAR performed the best in explaining inter-individual variance in muscular phenotypes. Conclusions Our results improve the understanding of inter-individual variance in muscular characteristics of older women and suggest a possible application of a sarcopenia-driven methylation score to muscle strength estimation in older women while the combination with a genetic score still needs to be further studied.