To the best of our knowledge, this was the first retrospective cohort study that investigated the causal relationship between serum uric acid and the risk of low muscle strength at different eGFR levels above 60yrs population. We revealed that in subjects with a high eGFR level, higher SUA levels were significantly associated with low muscle strength events independent of several risk factors, especially in females. At the same time, this correlation was no longer present when the eGFR level decreased.
These results help to clarify conflicts among previous studies. A cross-sectional study reported that association of higher uric acid levels with better grip strength [14], and the study by Molino-Love et al. concluded the same results that high uric acid levels remained independent positive predictors of grip strength after adjusting confounders [21]. These two studies, however, did not control for the contribution of eGFR in the model, neither ruled out the lower eGFR level nor adjusted eGFR as confounders, which may be unable to present the effect of uric acid on muscle strength properly. Another notable point is that some studies included populations under 60 years to assess sarcopenia, an age-related disease. The researchers suggested that a specific range of SUA positively correlated with better grip strength, whose results could be misleading due to including other non-specific populations [12, 13]. On the other hand, consistent with our findings, a Korean study excluding eGFR < 60 populations extracted data from KNHANES 2016 indicated that SUA is positively associated with increased grip strength in the elderly [22]. Nahas et al., adjusting eGFR and other confounders, showed that older men and women could take advantage of a high SUA level with better handgrip strength [15]. Thus, the present study and the abovementioned studies suggested that a better eGFR level may be a protective factor for serum uric acid levels to improve muscular strength.
We describe that different eGFR levels may cause the opposite effects of SUA to the risk of LMS in both men and women (Fig. 2,3). The mechanism by which a high serum level of UA is associated with a decreased risk of LMS in different eGFR remains unclear. Most studies regarding the relationship between circulating uric acid and handgrip strength believed that SUA had an antioxidant effect on lowering oxidative stress by scavenging reactive oxygen species (ROS) [12–16, 21, 22]. This hypothesis, however, may need more tests when it comes to the lower eGFR. The accumulation of SUA due to declined kidney function may be easily influenced by alteration in a particular chemical milieu in the organism, which tends to affect the antioxidant ability of uric acid [23]. Accumulation of bicarbonate, commonly seen in electrolyte disturbances in renal insufficiency, might cause the uric acid its ability to against tyrosine nitrosylation, a crucial mechanism of oxidative damage [24]. Furthermore, according to a recent study, some researchers believed that uric acid might contribute to oxidative stress rather than being an antioxidant in physiological conditions [11]. The authors demonstrated that uric acid might directly lead to the production of ROS, and the antioxidant properties of uric acid might be neutralized by ROS generated from xanthine oxidoreductase catalyzed reactions, which implicated that only exogenous uric acid administration may have the anti-oxidative stress effect. For instance, the administration of uric acid improved the clinical outcomes in patients with acute ischemic stroke [25], or uric acid injection in Parkinson’s disease mice showed a neuroprotective effect [26]. Thus, oxidative stress accumulation could diminish the age-related loss of muscle strength [27] and kidney function [8]. However, since the method of detecting accurate circulating xanthine oxidoreductase activity was not pervasive in clinical and few studies with exogenous uric acid to improve muscle strength, whether the uric acid act as an antioxidant in muscle wasting with aging requires further investigation.
Our results also showed that sex-specific impacts might affect SUA to LMS in different eGFR levels, indicating that women rather than men had a high eGFR level with SUA per-SD (3.99 ± 1.01) benefit from a 20% lower risk of LMS. This result was opposite to the previous study. A cohort study adjusted eGFR and other confounders by Veronese et al. demonstrated that hyperuricemia in men was associated with lower handgrip strength, while this relationship was not observed in women [16]. Besides the small sample size included in the studies, which compromised a study's statistical power, both studies did not include gender-specific biochemical parameters as confounders, which require further investigation in the future. Gender difference is a critical factor in the associations between physical activity and muscle strength during aging [28]. Additionally, AWGS 2019 consensus showed that sarcopenia was more prevalent in men than women, suggesting that sexual dimorphism may be present in the pathogenesis of the disease [2]. Sex hormones could be part of the differences between genders due to their effect on circulating uric acid, eGFR level, and muscle strength. During adolescence, higher testosterone and lower sex hormone-binding globulin were reported as the gender difference in circulating uric acid [29]. Testosterone levels were decreased with aging, which was associated with body composition, including low muscle mass, decreased strength, and increased muscular fatigue [30]. The high follicle-stimulating hormone was associated with declined eGFR in post-menopausal women [31]. Correspondingly, a mendelian randomization study from the United Kingdom Biobank population suggested that high sex hormone binding globulin was beneficial to better kidney function and lower risk of CKD in men [32]. In a prospective cohort study, Tsai et al. using data from MJ Health Screening Database, indicated that a low serum testosterone level (< 400 ng/dL) was significantly associated with a high SUA level (> 7 mg/dL) in males [33]. Additionally, testosterone therapy could increase serum uric acid pharmacologically [34]. The possible mechanism showed that testosterone exposure caused elevated UA production by simulating xanthine oxidase [35]. Further, the administration of testosterone could increase muscle mass [36], muscle strength, and muscle power [37]. All these studies suggested that testosterone may cause a gender-specific difference in the relationship between SUA and LMS. Therefore, the interaction of sex differences in both muscular strength and circulating uric acid in kidney function should gain more attention.
Despite the theory of sex hormones and oxidative stress, other possibilities could be affecting muscular strength with SUA level. First, chronic low-grade inflammation was pivotal in sarcopenia [38]. It is known that high SUA levels caused by decreased renal excretion may produce urate crystals, which would induce gout and nephrolithiasis [39], repeatedly leading to high circulating inflammatory mediators. A meta-analysis has shown that higher circulating inflammatory markers, such as CRP and IL-6, were associated with a decline in muscular strength [40]. In the present study, however, the results are still unfluctuating after solely adjusted hs-CRP, suggesting that inflammation is not the primary driver of muscle strength loss. Consistent with our results, a Danish cohort study demonstrated that only high levels of hs-CRP had weakly relationship with low muscular mass [41]. Second, metabolic syndrome may inversely influence muscular strength [27]. A prospective longitudinal study showed that high waist circumference was positively associated with lower handgrip strength [42]. Our results showed that the results remained robust after progressive adjusting BMI and waist circumference, lipid profiles, HbA1c, and medical history separately. Thus, metabolic syndrome could lead to decreased muscular strength, which may not be the crucial factor in the relationship between SUA and LMS by different eGFR. Third, the decreased hemoglobin level could affect muscle mass and strength through several mechanisms associated with sarcopenia in non-dialysis chronic kidney disease patients [43] and kidney transplant recipients [45]. In the present study, we also adjusted the hemoglobin alone, which did not change the results in women and men.
Limitations
Although our hypotheses were supported statistically, our study's results should be interpreted within its limitations. First, we did not evaluate whether the SUA levels changed during the follow-up and investigated the potential confounders of SUA levels at the baseline, including allopurinol and diuretics. Second, despite adjusting significant covariates separately, we cannot exclude the residual confounding of unmeasured factors in an observational study, including sex hormones, biomarkers of oxidative stress, nutritional status, and daily activity. Third, we did not have any information about gout history in this cohort. Moreover, the results should not be extrapolated to the presence of gout, which was related to SUA level and may affect the performance of muscle strength testing. Fourth, we focused on the population above 60yrs, which means that the results should not be extrapolated to those under 60 years, as they were “healthier” than the elderly.