Introduction
Sarcopenia is a syndrome characterized by a loss of muscle mass and strength, which often leads to functional impairment and adverse outcomes [
1]. This condition involves a restructuring of the overall muscle composition, including the transformation of muscle fibers and the infiltration of lipids [
2]. As a result, muscle power is diminished, and the risk of falls, mortality, disability, and hospitalization is elevated compared to individuals without sarcopenia [
3].
Extensive research has demonstrated that interleukins, particularly interleukin-6 (IL-6), play a critical role in the development of skeletal muscle wasting [
4]. They achieve this by activating molecular pathways that disrupt the balance between protein synthesis and catabolism [
5]. For example, IL-6 has catabolic effects on muscle proteins [
6]. In clinical settings, geriatric patients with acute infection-induced inflammation who received piroxicam, a non steroidal anti-inflammatory drug, showed a decreased level of IL-6 with better muscle performance. Several systematic reviews have consistently shown that elevated levels of inflammatory cytokines are inversely correlated with muscle strength and mass [
7‐
9]. On the other hand, therapeutic strategies that IL-6R antagonists, such as the use of tocilizumab, have shown promise in increasing muscle mass. IL-6 promotes inflammatory responses via the membrane-bound or circulating soluble IL-6R. Two studies demonstrated that administration of anti-mouse IL-6 receptor antibodies improved muscle mass in mice [
10,
11]. In a study by Tournadre et al., the use of tocilizumab was shown to have beneficial effects on lean mass without significant changes in fat mass in patients with rheumatoid arthritis [
12]. IL-6 and sIL-6R are important factors in the regulation of inflammation, but their effects on muscle mass and function suggest that the relationship for IL-6 and sIL-6R with sarcopenia is complex and may be mediated by other factors. Further research is needed to better understand the mechanisms underlying the association.
Mendelian randomization (MR) is an analytical approach that utilizes germline genetic markers as instrumental variables to assess potential risk factors [
13]. The random allocation of genetic variants from parents to offspring during gametogenesis provides protection against confounding factors typically encountered in observational studies and helps to mitigate issues of reverse causation [
14]. The growing availability of genetic association data for various traits and diseases has significantly enhanced the utility of MR methods for establishing reliable causal inferences. In particular, the inclusion of genome-wide association study (GWAS) data from large-scale consortia has the potential to enhance the statistical power of MR analyses for detecting causal effects [
15]. MR provide a causal inference approach to establish whether the association between IL-6 or sIL6 and sarcopenia is causal or merely a correlation. Therefore, the aim of this study was to comprehensively investigate the causal relation for IL-6 or sIL6 with sarcopenia using a two-sample Mendelian randomization approach, and to determine whether targeting these factors may be a viable approach to preventing or treating muscle loss.
Disscusion
This MR study demonstrated a significant and negative association between IL-6R and hand grip strength. However, no evidence of an association between IL-6 and sarcopenia traits was found. These findings offer new insights into the impact of interleukins on hand grip strength.
Immune aging is closely associated with the development of sarcopenia, leading to the loss of skeletal muscle mass and function [
30]. Inflammatory parameters have been shown to be inversely related to hand grip strength [
31], suggesting a potential role of the immune system in skeletal muscle protein metabolism during aging [
32]. IL-6, as one of the inflammatory factors, plays a crucial role in modulating muscle anabolism or catabolism in response to tissue damage or infection. Previous meta-analyses have consistently demonstrated a negative association between IL-6 and muscle strength and mass. However, it is important to consider the potential influence of reverse causation bias or confounding factors in these associations [
9]. Prolonged exposure to IL-6 has been associated with the promotion of muscle atrophy through the suppression of muscle anabolism and energy homeostasis, as well as the direct induction of muscle catabolism [
33]. During the development of sarcopenia, there is an increase in the secretion of inflammatory factors, contributing to a low-grade inflammatory state. Moreover, skeletal muscle mass and function decline with age, accompanied by a decrease in the synthesis and secretion of myogenic inflammatory factors, which disrupts skeletal muscle energy metabolism [
34]. However, no relationship between IL-6 and sarcopenia traits was observed in this study. This inconsistency may be due to previous studies that found the associations through observational studies, which are prone to confounding and reverse causation. In contrast, MR analysis can help to overcome these limitations by using genetic variants that are less likely to be influenced by confounding factors [
35]. It is also possible that IL-6R has a different biological function and effect on muscle strength compared to IL-6. This may explain why our MR analysis did not find a significant association with sarcopenia traits for IL-6 but for IL-6R. Overall, our findings suggest that the previously reported association between IL-6 and muscle mass may not be causal and that IL-6R may have a direct effect on hand grip strength. However, further studies are needed to confirm these findings and to investigate the underlying biological mechanisms.
Furthermore, the methods used to measure muscle mass can vary between studies, and this can contribute to differences in findings. ALM is a commonly used measure of muscle mass in the context of sarcopenia, but it is not the only measure available [
36]. Other measures, such as whole-body muscle mass or muscle cross-sectional area, may be more appropriate in certain contexts. Additionally, the way in which ALM is calculated (i.e., whether it is divided by height, weight, or BMI) can also impact the results.
Our study has several limitations that should be considered when interpreting our findings. First, our analysis was conducted using large-scale GWAS data, which may not represent the entire population. Additionally, the sample size for the IL-6 was relatively small, which may limit the generalizability of your findings. Second, While MR can help to address issues of confounding, there may be additional confounders that were not accounted for in our study. For example, factors such as diet, physical activity, or medication use may influence both interleukin levels and muscle mass. Third, we only focused on IL-6R and IL-6 and did not examine the full range of interleukins that may be relevant to muscle mass. Other interleukins may have different effects on muscle mass, and examining a broader range of interleukins may provide a more complete picture of their relationship with muscle mass.
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