근육 대사에서 β2-Microglobulin의 작용기전 및 효과 검증에 관한 연구

Abstract

Background: β2-Microglobulin (B2M) has garnered considerable interest as a potential pro-aging factor, leading to speculation about its involvement in muscle metabolism and the development of sarcopenia, a key component of aging phenotypes. To explore this hypothesis, we conducted a comprehensive investigation into the impact of B2M on cellular and animal muscle biology, as well as its clinical implications concerning sarcopenia parameters in older individuals.

Methods: In vitro myogenesis was induced in mouse C2C12 myoblasts with 2% horse serum. For in vivo research, C57BL/6 mice aged 3 months were intraperitoneally given 250 μg of B2M daily, and muscular alterations were assessed one month later. Human blood samples were obtained from 158 participants who underwent assessments of muscle mass and function at an outpatient geriatric clinic affiliated with a teaching hospital. Sarcopenia and associated parameters were assessed using cutoff values specifically tailored for the Asian population. The concentration of serum B2M was quantified through an enzyme-linked immunosorbent assay.

Results: Treatment with recombinant B2M exhibited a dose-dependent inhibition of myogenesis from mouse C2C12 myoblasts and consistently lowered the expression of myogenic differentiation markers. Furthermore, B2M notably elevated intracellular levels of reactive oxygen species (ROS) in myotubes, and administration of N-acetyl cysteine, a potent biological thiol antioxidant, reversed the decrease of myotube area, myotube area per myotube, nucleus number per myotube, and fusion index by B2M through mitigating oxidative stress. Animal experiments showed that mice with systemic B2M treatment exhibited significantly smaller cross-sectional area of tibialis anterior and soleus muscle, weaker grip strength, shorter grid hanging time, and decreased latency time to fall off the rotating rod, compared to untreated controls. In a clinical study, serum B2M levels were inversely associated with grip strength, usual gait speed and short physical performance battery (SPPB) total score after adjustment for age, sex, and body mass index, whereas sarcopenia phenotype score showed a positive association. Consistently, higher serum B2M levels were associated with higher risk for weak grip strength, slow gait speed, low SPPB total score, and poor physical performance.

Conclusion: These results provide experimental evidence that B2M exerted detrimental effects on muscle metabolism mainly by increasing oxidative stress. Furthermore, we made an effort to translate the results of in vitro and animal research into clinical implication and found that circulating B2M could be one of blood-based biomarkers to assess poor muscle health in older adults.