The present study, an epigenetic nationwide cohort study using KOGES data, compared the elderly with relatively sufficient muscle mass and those with relatively insufficient muscle mass based on the MMI for each gender. The demographic study of men showed a significant decrease in MMI with age. However, in the case of women, there was no significant difference in MMI according to age. According to Yanping Du et al., males had a higher incidence of sarcopenia than females using the criteria of the Asian Working Group for Sarcopenia.(19) In the physical activity category of men, a steady state was found to be significantly higher in the lower 30% of the MMI group. On the other hand, in the case of women, hard activity was significantly higher in the MMI top 30% group. The history of the disease did not show any significant results in both men and women.
Sarcopenia is characterized by somatic changes with age and is described as skeletal muscle loss.(20) In addition, differences in the incidence of sarcopenia between men and women have been studied. In particular, in the case of men, the decrease in muscle mass and strength is more prominent than in women.(21) According to Gallagher et al., total apendicular muscle mass loss according to age in men and women was 15% and 11%.(22) Over a three-year period, older men lost twice as much absolute knee extensor strength as women in the Health ABC trial.(23) Notably, a decrease in physical function in females is more evident in people aged 65–74 years.(24) In addition, women exhibited lower functional impairment, fracture risk, and loss of independence than men, according to the clinical trial.(25)
In the present study, we examined the change in the methylation profile according to muscle mass loss in males and females. In the enrichment analysis, genes related to autoimmune-related disease pathways such as allograft rejection, graft-versus-host disease, type 1 diabetes mellitus, and autoimmune thyroid disease were significantly present in the male group DMRs. Studies on the relationship between sarcopenia and autoimmune diseases have been ongoing. Among them, research on rheumatoid arthritis, a representative autoimmune disease, is the most active. Cross-sectional studies of RA and sarcopenia revealed a higher incidence of sarcopenia in RA patients.25–28 According to Hyo Jin An et al., sarcopenia prevalence ranged from 10.1 to 45.1 percent, with a median of 29.1 percent in the RA studies.(30) In addition, the association between sarcopenia and inflammatory bowel disease, and type 1 diabetes mellitus has also been studied.(31, 32) However, there have been few studies on the epigenetic effect on sarcopenia in men compared to women in relation to autoimmune diseases.
Patients with sarcopenia are at an increased risk of hip fracture due to falls because of weakened muscle strength and poor balance.(33) According to Kang et al, the immunological and inflammatory reactions in the lungs were increased following a bone fracture.(34) Therefore, according to this study, in men, hip fracture due to sarcopenia and pulmonary inflammation due to immune changes in the lungs seem to have a positive correlation. Alternatively, since both sarcopenia and pneumonia are immune-related diseases, the incidence could be higher in patients with autoimmune diseases. Further studies on the co-occurrence rate of sarcopenia and pneumonia in patients with immune diseases are needed.
In the enrichment analysis of the female group, DMRs related to ubiquitin-mediated proteolysis, MAPK signaling pathway, and NF-kappa B signaling pathway were significant. MAPK protein affects skeletal muscle by several signaling modules, such as ERK1/2, p38 MAPK, and ERK5.(35) The ubiquitin-proteasome system is a key regulator of protein breakdown, allowing regulatory and structural proteins to be degraded selectively.(36) In addition, NF-kappa B can induce skeletal muscle protein degradation by upregulating the expression of several proteins in the ubiquitin-proteasome system.(37) Muscle degeneration which is induced by the ubiquitin-proteasome system, have a strong influence on aging sarcopenia;(38) catabolic effects in skeletal muscle by MuRF-1 and MAFbx, which are representative factors in the ubiquitin-proteasome system, may be the main cause of sarcopenia.(39) Therefore, the results of this female epigenetic study suggest that protein degradation through the signaling pathway-like ubiquitin-proteasome system is an important cause of muscle mass loss in the pathogenesis of sarcopenia.
In both male and female circos plots in this study, the most significant region was found in the short arm of chromosome 9. According to a study by Ikeuchi, distal myopathy with rimmed vacuoles, which is a neuromuscular disorder and causes skeletal muscle weakness, showed that chromosome 9 is affected by the gene loci.(40) Also, in another study, rs7022373, the most significant SNP in the pathogenesis of sarcopenia, is located on chromosome 9.(41) However, in epigenetic studies, there are only a few studies on chromosomes that are highly related to sarcopenia, therefore, further studies are needed.
Limitation
The present study has several limitations. First, we measured the MMI of the subjects, but not the grip strength used in the diagnosis of sarcopenia at the same time. Second, the age range of the subjects ranged from 40 to 69, which is included in the middle-aged. However, prevention of sarcopenia in middle age is necessary for the elderly’s quality of life. Third, there were no common results between DMRs and genotypes. Further studies with extended cohorts are necessary.