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

Background

An 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.

Methods

DNA 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.

Results

Seven 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.

Conclusions

These 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.