Epigenome‐wide association study of sarcopenia: findings from the Hertfordshire Sarcopenia Study (HSS)

Abstract

Background Sarcopenia is the age‐related loss of muscle mass, strength, and function. Epigenetic processes such as DNA methylation, which integrate both genetic and environmental exposures, have been suggested to contribute to the development of sarcopenia. This study aimed to determine whether differences in the muscle methylome are associated with sarcopenia and its component measures: grip strength, appendicular lean mass index (ALMi), and gait speed. Methods Using the Infinium Human MethylationEPIC BeadChip, we measured DNA methylation in vastus lateralis muscle biopsies of 83 male participants (12 with sarcopenia) with a mean (standard deviation) age of 75.7 (3.6) years from the Hertfordshire Sarcopenia Study (HSS) and Hertfordshire Sarcopenia Study extension (HSSe) and examined associations with sarcopenia and its components. Pathway, histone mark, and transcription factor enrichment of the differentially methylated CpGs (dmCpGs) were determined, and sodium bisulfite pyrosequencing was used to validate the sarcopenia‐associated dmCpGs. Human primary myoblasts (n = 6) isolated from vastus lateralis muscle biopsies from male individuals from HSSe were treated with the EZH2 inhibitor GSK343 to assess how perturbations in epigenetic processes may impact myoblast differentiation and fusion, measured by PAX7 and MYHC immunocytochemistry, and mitochondrial bioenergetics determined using the Seahorse XF96. Results Sarcopenia was associated with differential methylation at 176 dmCpGs (false discovery rate ≤ 0.05) and 141 differentially methylated regions (Stouffer ≤ 0.05). The sarcopenia‐associated dmCpGs were enriched in genes associated with myotube fusion (P = 1.40E‐03), oxidative phosphorylation (P = 2.78E‐02), and voltage‐gated calcium channels (P = 1.59E‐04). ALMi was associated with 71 dmCpGs, grip strength with 49 dmCpGs, and gait speed with 23 dmCpGs (false discovery rate ≤ 0.05). There was significant overlap between the dmCpGs associated with sarcopenia and ALMi (P = 3.4E‐35), sarcopenia and gait speed (P = 4.78E‐03), and sarcopenia and grip strength (P = 7.55E‐06). There was also an over‐representation of the sarcopenia, ALMi, grip strength, and gait speed‐associated dmCpGs with sites of H3K27 trimethylation (all P ≤ 0.05) and amongst EZH2 target genes (all P ≤ 0.05). Furthermore, treatment of human primary myoblasts with the EZH2 inhibitor GSK343 inhibitor led to an increase in PAX7 expression (P ≤ 0.05), decreased myotube fusion (P = 0.043), and an increase in ATP production (P = 0.008), with alterations in the DNA methylation of genes involved in oxidative phosphorylation and myogenesis. Conclusions These findings show that differences in the muscle methylome are associated with sarcopenia and individual measures of muscle mass, strength, and function in older individuals. This suggests that changes in the epigenetic regulation of genes may contribute to impaired muscle function in later life.

Skeletal muscle DNA methylation: Effects of exercise and HIV

“…Thus, variation in methylation due to HIV serostatus was selected out when using MEAT but was apparent in the genome-wide analyses (Figure 2). In line with this rationale, no study using MEAT, including the present one, has identified associations between SkM epigenetic age and sarcopenia (Antoun et al, 2022), physical function (Sillanpaa et al, 2021) or exercise training (Gorski et al, 2023).…”

“…As noted byLindholm et al (2014), the changes in DNA methylation in response to environmental conditions (i.e., exercise) are slight when compared to disease-related conditions (i.e., HIV infection). Nonetheless, aerobic and resistance exercise training are associated with a shift toward a "younger" methylome(Voisin et al, 2023), thus supporting that exercise training triggers some effects that oppose aging.By way of genome-wide analyses, we found that DMPs were hypermethylated in PWH compared to controls before and after exercise training Antoun et al (2022). found that in SkM of older men, 53% of DMPs distinguished by the presence of sarcopenia were hypermethylated.…”

Epigenetic Mechanisms of Aging and Aging-Associated Diseases

“…Indeed, the authors demonstrated that the differentially methylated CpGs (dmCpGs) were enriched in genes involved in oxidative phosphorylation, voltage-gated calcium channels, and myotube fusion. Finally, by examining the chromatin architecture of the sarcopenia-related dmCpGs, the authors identified that they were contained at EZH2 target genes and at regions of H3K27 trimethylation [ 218 ].…”

“…In recent years, with the deepening of the research on the pathological mechanism of osteoporosis, the research on epigenetics has made significant inroad. Studies have demonstrated that epigenetic mechanisms are closely related to osteogenesis, bone remodeling, osteogenic differentiation, and other bone metabolism-related processes [ 218 ]. Reppe et al revealed an increasing level of CpG methylation in SOST gene promoter region in 27 postmenopausal women with osteoporosis compared to 36 healthy controls [ 219 ].…”

Epigenome-wide association study identifies DNA methylation loci associated with handgrip strength in Chinese monozygotic twins

“…Several studies have reported a hypermethylated state in skeletal muscle tissue in older subjects compared to younger subjects ( Zykovich et al, 2014 ; Turner et al, 2020 ). There are multiple epigenome-wide association studies (EWAS) of sarcopenia or muscle mass and strength among people of European ancestry ( Livshits et al, 2016 ; Voisin et al, 2021 ; Antoun et al, 2022 ). These studies have identified many CpG loci and differentially methylated regions (DMRs) that may be associated with muscle strength.…”