Early Life Environment Is Associated With Differential DNA Methylation of Primary Myoblasts From Older Individuals

ABSTRACTBackgroundAn adverse early‐life environment is associated with impaired muscle mass and function in later life, with epigenetic processes proposed as mediators. The aim of this study was to investigate whether early‐life exposures were associated with altered patterns of DNA methylation in cultured myoblasts isolated from community‐dwelling older individuals and whether the changes in DNA methylation contributed to impaired muscle function and muscle‐related pathologies in later life.MethodsDNA methylation (Infinium HumanMethylationEPIC BeadChip) was measured in proliferating myoblast cultures from vastus lateralis biopsies (119 male/females, median age 77.8 years) from the UK Hertfordshire Sarcopenia Study extension (HSSe). Analyses examined differentially methylated CpG sites (dmCpG), regions (DMRs) and pathways associated with birthweight, weight at 1 year, conditional growth during infancy and frequency of contemporaneously recorded childhood illnesses from birth to age 1 year and from age 1 to 5 years. RT‐PCR was used to examine the correlation between methylation and expression. Associations between dmCpGs and muscle‐related pathologies including sarcopenia, its definitional components (grip strength, appendicular lean mass index [ALMi] and gait speed) and impaired glucose‐insulin metabolism were also examined.ResultsSeven myoblast dmCpGs were associated (FDR ≤ 0.05) with birthweight, eight with weight at 1 year and six with conditional growth during infancy, with dmCpGs enriched in metabolic and nutrient sensing pathways. One differentially methylated region (DMR) (Stouffer ≤ 0.05) was associated with birthweight, located within the Branched Chain Amino Acid Transaminase 1 (BCAT1) gene, with two of the CpGs sites positively associated with BCAT1 transcript levels (cg05197760: p = 1.73 × 10−2, cg13966241: p = 3.31 × 10−2). There were 16 and 53 dmCpGs significantly associated (FDR ≤ 0.05) with the frequency of childhood illnesses from birth to 1 year and from 1 to 5 years, respectively, with dmCpGs enriched in signal transduction and stress pathways. Of the 90 dmCpGs associated with early‐life size or infections, five were also associated with later‐life ALMi, four with grip strength, one with sarcopenia, four with HOMA2‐IR and fasting insulin levels and two with fasting glucose levels (all p ≤ 0.05). cg13939055 (located within a long noncoding RNA) mediated the relations of increased frequency of childhood illnesses from age 1 to 5 years with HOMA2‐IR (p = 3.3 × 10−2) and fasting insulin (p = 3.3 × 10−2) in later life.ConclusionsThese findings suggest that infant growth and infections during early‐life influence the methylome of myoblasts in later life. This supports the premise that early life is a critical developmental window that can influence later‐life muscle resilience through epigenetic modulation.