In this study, we employed a comprehensive analytical approach to investigate the relationship between iron status and sarcopenia. By analyzing pooled data from GWAS conducted on European populations, our study aimed to establish a causal relationship between iron status and sarcopenia-related traits. Through UVMR and MVMR, we consistently found that genetically predicted serum ferritin levels exerted a significant causal effect on appendicular lean mass.
Our UVMR and MVMR analyses provide evidence that increased serum ferritin levels may have a detrimental causal effect on appendicular lean mass. This finding is in line with previous observational studies showing iron overload associates with adverse muscle outcomes [26, 50, 51]. About 30% of the body's iron is stored in the form of ferritin or hemosiderin, so serum ferritin is a good indicator of the body's iron reserves [52]. High ferritin levels indicate iron overload and saturation of transferrin, allowing non-transferrin bound iron to accumulate and catalyse reactive oxygen species generation. Oxygen-free radicals have the potential to initiate mitochondrial RNA peroxidation. This, in turn, triggers the activation of mitochondrial permeability transition pores (mPTP), resulting in the release of cytochrome C into the cytoplasm. Subsequently, caspase-3 is activated, ultimately leading to apoptosis in skeletal muscle cells [53–55]. In addition, some researchers have found that iron overload may affect the function of muscle satellite cells through ferroptosis, affecting the repair of damaged skeletal muscle [56]. Animal studies indicate that as iron load in skeletal muscles elevates, there's a reduction in muscle mass and cell atrophy. Concurrently, Akt-FOXO3 activates, and levels of atrogin-1 and MuRF1, ubiquitination markers linked to muscle cell atrophy, increase[57]. All of the above underlying mechanisms could explain the relationship between serum ferritin and skeletal muscle mass in the extremities. The lack of associations for handgrip strength, walking pace and ferritin also implies that higher ferritin may preferentially induce muscle mass loss rather than strength or physical performance decline.
We observed that TIBC exhibited a potential risk association with sarcopenia, leading to a negative impact on appendicular lean mass. On the other hand, our reverse MR result indicates that decreased appendicular lean mass could elevate TIBC. One possible explanation is that under normal circumstances, ferritin can be disassembled by autophagy, releasing iron for cellular processes[58]. However, skeletal muscles exhibit impaired autophagy with age[59]. This could lead to two scenarios: the inappropriate sequestration of iron into ferritin or a failure in ferritin breakdown. Both result in a reduction of cellular free iron, causing functional iron deficiency, which then affects the normal energy metabolism of skeletal muscle, leading to skeletal muscle atrophy [3]. The above underlying mechanisms could similarly explain the significant association of reduced TSAT with the decrease in appendicular lean mass. This is because elevated serum ferritin associated with decreased TSAT is often typical of functional iron deficiency. Notably, under the Bonferroni correction significance level, no correlation was observed between TIBC and TSAT with appendicular lean mass. These findings imply that future investigations should include larger GWAS datasets and consider conducting meta-analyses using data from multiple sources to provide further insights into the relationship between these variables.
Interestingly, no significant associations were found between serum iron and sarcopenia traits in our study. To date, limited research has been conducted to investigate this particular relationship. Bartali et al. [60] conducted a longitudinal study involving 698 participants but failed to identify a significant link between serum iron levels and physical function. Similarly, a prior systematic review[61] also failed to demonstrate a significant relationship between serum iron and sarcopenia. A reason could be that these markers reflect iron availability in the short term, while ferritin indicates long-term iron storage and may better predict chronic health risks.
The present study possesses several notable strengths. To the best of our knowledge, this study represents the first attempt to explore the causal associations between iron status and sarcopenia using Mendelian randomization, leveraging large-scale GWAS data. The implementation of MR design stands as a significant strength, as it effectively mitigates residual confounding and other biases, thereby enhancing the strength of causal inferences drawn[62]. Our employment of UVMR and MVMR analyses surpasses previous observational studies, as we have leveraged summary data derived from GWASs featuring an extensive sample size and a vast number of SNPs. Furthermore, the outcomes obtained are characterized by robustness and reliability, demonstrated by the absence of heterogeneity or pleiotropic effects.
However, several limitations are inherent in our study. Primarily, the genetic variant data primarily relied upon GWASs conducted on individuals of European descent, which may restrict the generalizability of our findings to the broader population. Nonetheless, the restriction of participant descent serves to minimize the potential confounding effects stemming from population admixture. Secondly, the utilization of summary-level data imposes constraints on the range of analyses that can be performed, including the exploration of nonlinear relationships between exposure and outcomes, as well as stratified analyses based on age or sex. Lastly, it is important to note that while efforts were made to calculate type 1 error rates below 0.05, the possibility of weak instrumental variable bias resulting from sample overlap could not be entirely eliminated, as both exposure and outcome data were partially obtained from UKBs.