Detrimental Effects of β2-Microglobulin on Muscle Metabolism: Evidence From In Vitro, Animal and Human Research

β2-Microglobulin (B2M) has garnered considerable interest as a potential pro-ageing factor, leading to speculation about its involvement in muscle metabolism and the development of sarcopenia, a key component of ageing 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.

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 cut-off values specifically tailored for the Asian population. The concentration of serum B2M was quantified through an enzyme-linked immunosorbent assay.

Recombinant B2M inhibited in vitro myogenesis by increasing intracellular reactive oxygen species (ROS) production. Furthermore, B2M significantly induced differential myotube atrophy via ROS-mediated ITGB1 downregulation, leading to impaired activation of the FAK/AKT/ERK signalling cascade and enhanced nuclear translocation of FoxO transcription factors. 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.

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.