Sarcopenia, a progressive and prevalent skeletal muscle disorder, is intricately associated with a range of adverse outcomes encompassing falls, functional deterioration, frailty, and mortality (1). As expounded by the European Working Group on Sarcopenia in Older People (EWGSOP)-2, sarcopenia manifests as a diminution in muscular strength accompanied by a reduction in muscle mass, the severity of which determines the extent of functional impairment (2). Statistical data reveal that sarcopenia currently affects approximately 10% to 16% of the elderly population worldwide (3). However, the prevalence of this condition is projected to soar over the course of the next four decades, impacting over 200 million individuals globally (4). Of particular note, elderly patients admitted to hospitals who are afflicted by sarcopenia incur hospitalization expenses that exceed fivefold compared to those without sarcopenia, exacting a considerable toll on the healthcare system (5).

Urate, the ultimate byproduct arising from the metabolic breakdown of purines, exerts both potentially beneficial and detrimental consequences (6). Substantiated investigations have established that uric acid exhibits pro-inflammatory properties, intricately associated with the initiation and progression of a multitude of ailments, including chronic kidney disease, cardiovascular disease, hypertension, diabetes, and metabolic syndrome (7). Nevertheless, urate assumes a pivotal role as an antioxidant, effectively neutralizing oxygen free radicals, manifesting as a crucial combatant against the perils of oxidative stress (8). Low levels of serum uric acid have been associated with various adverse health outcomes, including increased all-cause mortality and the progression of neurodegenerative diseases like Parkinson’s, Alzheimer’s, and amyotrophic lateral sclerosis (9).

With advancing age, the capacity of human musculature to regulate Reactive Oxygen Species (ROS) levels gradually wanes, compromising the homeostasis of intracellular milieu and instigating an escalated state of oxidative stress (10). Mounting evidence underscores the crucial role of augmented oxidative stress and inflammation in the pathogenesis of muscle loss and functional decline (11, 12). However, the relationship between uric acid and sarcopenia remains obscured, as uncertainties persist regarding the intricate interplay between antioxidant stress and inflammatory mechanisms. A retrospective study unveiled a noteworthy correlation between hyperuricemia and elevated muscle mass and strength, suggesting a conceivable protective effect of uric acid against sarcopenia (13). Furthermore, an investigation focusing on renal transplant patients divulged a positive association between serum urate levels and both muscle mass and strength (14). In the western region of China, a cross-sectional study conducted among the adult population aged over 50 years revealed the correlation between elevated uric acid levels and augmented muscle mass as well as grip strength, confirming that the potential role of heightened serum urate levels in impeding the progression of sarcopenia (15). However, the cross-sectional study conducted in the United States reported that participants categorized within the highest group of serum uric acid concentration (>8 mg/dL) faced twice the likelihood of developing sarcopenia compared to those in the lowest concentration group (<6 mg/dL), implicating that hyperuricemia serves as an independent risk factor associated with sarcopenia (16). Nevertheless, it is important to note that observational studies inherently possess certain limitations that prevent them from eliminating the impact of reverse causality and confounding factors, which possibly introduce biased conclusions (17).

Mendelian randomization (MR) analysis is a method rooted in Mendel’s laws of inheritance that have gained increasing prominence in establishing plausible causal associations between risk factors and disease outcomes (18). This analytical approach capitalizes on the random classification properties of genetic variants and leverages these variants associated with environmental exposures as instrumental variables (IVs) to assess the associations between exposures and outcomes (19). By virtue of genetic variants being randomly assigned during conception prior to disease onset, MR analysis effectively circumvents the influence of confounding factors, measurement errors, and reverse causality, greatly improving the reliability of study results (20).

Recent MR investigations have delved into the causal association between sarcopenia and a myriad of factors, such as lifestyle, coronary heart disease, osteoarthritis, major depressive disorder and autoimmune conditions (21–25). However, MR studies remains devoid of any pertinent investigations concerning the association between urate and sarcopenia. Consequently, we have undertaken the application of MR analysis to elucidate the causal link between genetically determined serum urate levels and sarcopenia.

To the best of our acknowledge, this investigation represents the inaugural genetic exploration with the purpose of unraveling the potential causal association linking serum urate levels and sarcopenia. By virtue of our MR analysis, we uncovered no substantiated indications endorsing the causal association between serum urate levels and sarcopenia. Similarly, our study did not reveal any discernible causal effect of sarcopenia on serum urate levels.

The majority of previous observational investigations has indicated a positive correlation between serum urate levels and sarcopenia. However, these findings remain uncertain, as divergent conclusions have been presented by several studies. Multiple cross-sectional studies conducted in China (39), Japan (40), Korea (41), the United States (42), and Italy (43) have intimated the potential protective effect of augmented serum urate levels on muscle strength. A longitudinally conducted follow-up study spanning three years demonstrated that escalated uric acid levels were prospectively and independently associated with improved muscle strength (44). Conversely, a decade-long longitudinal investigation, focusing on a Tasmanian cohort of elderly individuals, revealed the significant association between elevated urate concentrations and the rate of muscle strength degeneration (45). Additionally, a Japanese study encompassing individuals aged 30 and above identified a distinctive inverse-J relationship between serum urate quartiles and muscle strength (46). Similarly, the relationship between urate levels and muscle mass remains uncertain, with the establishment of a causal association yet to be ascertained. Two prospective studies from Israel (47) and China (48) have provided evidence of the positive association between serum urate levels and muscle mass. Nevertheless, a prospective study executed among Spanish community-dwelling elderly adults found an inverse association between urate levels and muscle mass (49). Additionally, a cross-sectional study conducted in the United States did not identify any substantial correlation between serum uric acid and muscle mass (50). It is important to acknowledge that these observational studies are susceptible to the influence of confounding factors and the potential concern of reverse causality, which poses challenges in establishing the causal link between serum uric acid levels and muscle strength and mass. Nevertheless, these limitations can be mitigated through the application of MR studies.

Oxidative stress denotes an intricate disturbance in the equilibrium between oxidative and antioxidant activity within the biological system, culminating in the excessive production and accumulation of oxidative radicals, which inflicts deleterious effects upon cells and tissues (51). A multitude of investigations has substantiated the pivotal engagement of oxidative stress in the pathogenesis of sarcopenia-induced muscle loss (52). Oxidative stress has the capacity to trigger the occurrence of oxidative protein damage in muscle cells, wherein the structural integrity of proteins is compromised by various oxidative modifications, including protein oxidation and hydroxylation. Consequently, the functionality and stability of muscular proteins are diminished, impeding their intrinsic physiological functions (53). Furthermore, mitochondria, acknowledged as the primary source of ROS production in skeletal muscle, emerge as susceptible targets of the oxidative onslaught. The sustained impact of oxidative stress impairs mitochondrial function, compromising the energy supply of muscle cells, and ultimately resulting in the waning of muscular performance (54–56). Simultaneously, oxidative stress exerts severe interference with the repair system of mitochondrial DNA, undermining the regenerative capacity of muscle tissue (57). Furthermore, it is noteworthy that oxidative stress has the ability to elicit an inflammatory response within muscle tissue. The escalated production of ROS activates signaling pathways associated with inflammation, resulting in the release of inflammatory cytokines and chemokines (58, 59). While the inflammatory response serves as a defensive mechanism against oxidative stress to a certain extent, an excessive or protracted inflammatory reaction can inflict detrimental consequences upon muscle tissue, culminating in damage and degeneration (60, 61). In this intricate milieu, the emergence of uric acid assumes a distinctive role. With its profound antioxidative properties, uric acid efficiently scavenges ROS, asserting dominance over approximately two-thirds of the overall plasma antioxidant capacity (8, 62). Elevated levels of uric acid have consistently demonstrated a positive correlation with heightened serum antioxidant capacity and enhanced resistance against oxidative stress (63). These findings postulate that uric acid may assume a protective function in mitigating muscle loss by fortifying the defense against oxidative stress.

The significance of inflammation in the pathogenesis and progression of sarcopenia cannot be disregarded, as an abundance of studies has revealed a negative correlation between elevated levels of inflammatory cytokines and both muscular strength and mass (64, 65). Inflammatory cytokines possess the capacity to activate diverse molecular pathways connected to skeletal muscle atrophy, precipitating an imbalance in protein synthesis and catabolism, consequently expediting the process of muscular wasting (66). Notably, uric acid has been shown to exhibit an intimate connection with the inflammatory response (67, 68). Uric acid is capable of directly stimulating mitogen-activated protein kinases, instigating inflammatory signaling pathways, and augmenting the production of pro-inflammatory cytokines including interleukin 1(IL-1), interleukin 6(IL-6), and tumor necrosis factor (TNF), which exert pro-inflammatory effects independent of ROS (69, 70). Consequently, the inflammatory response elicited by uric acid may exert potentially detrimental effects on muscle mass and function. This implies that while uric acid may harbor a protective effect on muscle, it also gives rise to unfavorable consequences. However, the ultimate ramifications of uric acid-induced inflammation and antioxidant stress on muscle remain uncertain at present. The analysis conducted in the present MR study unequivocally establishes no association between urate levels and both muscle strength and mass, which engenders the speculation that such an outcome may arise from a compensatory interplay between uric acid-induced inflammation and the counteractive influence of antioxidative stress.

The proposition that elderly individuals afflicted with asymptomatic hyperuricemia could refrain from pursuing aggressive uric acid-lowering therapy to impede the advancement of sarcopenia (13), is unequivocally disproved by our findings. It is of paramount importance to acknowledge that the presence of hyperuricemia, even in the absence of symptoms, manifests a profound correlation with the emergence of various comorbidities, type 2 diabetes mellitus, and cardiovascular disease (71). Consequently, it becomes imperative to approach the correlation between uric acid and sarcopenia with the utmost caution, lest capitulating to the administration of misguided interventions that have the potential to engender deleterious consequences. Furthermore, it is imperative to acknowledge the potential heterogeneity within the populace of distinct clinical subcategories of sarcopenia. Genetic variations present in individuals exhibiting various subtypes of sarcopenia may elicit divergent responses to serum uric acid concentrations. Consequently, it becomes evident that future investigations should be directed towards a comprehensive exploration of these nuanced distinctions.

Our investigation boasts several strengths. Primarily, the utilization of the MR analysis harnessed genetic variation, effectively attenuating the influence of potential confounding factors and reverse causality. Secondly, we employed a diverse array of methods within our MR analysis to ensure the accuracy and validity of the results. By incorporating multiple statistical models in our sensitivity analysis, we effectively assessed the consistency of the primary outcomes, furnishing compelling and reliable evidence. Finally, our study was underpinned by the selection of the most recent and dependable data from a substantial sample size. Nevertheless, Certain limitations should be acknowledged in our study. Firstly, the composition of our study population was exclusively European, impeding the direct generalization of our results to individuals from different ethnic backgrounds and distinct cultural milieus. Secondly, old age and an individual’s specific health condition are profoundly intertwined with serum urate levels and development of sarcopenia. Regrettably, we were precluded from investigating these variables in greater depth owing to the unavailability of individual-level data. Furthermore, the utilization of ALM as a gauge of muscle mass may introduce a measure of inaccuracy, owing to potential biases stemming from other non-fat soft tissue constituents. Lastly, although grip strength serves as an objective and common marker of muscle strength, it predominantly represents upper body potency, failing short of comprehensively capturing the strength across the entire body.

In conclusion, our bi-directional MR analysis found no causal association between serum urate levels and sarcopenia. In light of this finding, it is incumbent upon us to exercise prudence when considering interventions targeting serum urate levels as a means to postpone the onset or progression of sarcopenia.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

FF and YL took involved in the study design. YL and XW conducted clinical assessments. YS, WY and JZ were responsible for data collection. YL, and XW analyzed the data. The text was written by YL and was reviewed by additional writers. All the authors contributed to this article and approved the submitted version.