Our population-based cross-sectional study has demonstrated that hyperuricemia is associated with poor muscle strength after adjustment for potential confounders in Japanese adult men aged 30–83 years. Furthermore, we have found a significant inverted J-shaped curve between serum UA quartiles and muscle strength.
To the best of our knowledge, this study shows for the first time that muscle strength was much lower in persons with hyperuricemia than in those without hyperuricemia. This study supports previous findings of low relative skeletal muscle mass in persons with hyperuricemia, which reported that participants with serum UA levels >8 mg/dL had 2 times the risk of sarcopenia (assessed on the basis of skeletal muscle mass) compared with those with <6 mg/dL after adjustment for other covariates in a population of 40 years old and older
. In addition, the observed inverted J-shaped associations of serum UA levels with muscle strength in our investigation were in accordance with another cross-sectional population study in which 966 elderly subjects were analyzed
. The study showed that participants in the middle serum UA quintile tended to have less disability in instrumental activities of daily living and better lower extremity function than those with higher or lower UA levels. Although these results are cross-sectional, keeping serum UA at an optimal level may contribute to maintaining skeletal muscle mass. It is interesting to note that most of the epidemiologic studies have indicated that serum UA levels showed a J-shaped association with cardiovascular events
 and all-cause mortality
[30, 31], implying that both a low and a high UA level may lead to a higher risk of cardiovascular event or mortality.
On the other hand, a most recent prospective cohort study was the first to report a linear association of circulating UA levels with grip strength or/and leg extension power in elderly persons during a 3-year follow-up period
. Given its powerful antioxidant capacity, UA may protect skeletal muscle function from ROS-induced protein oxidative damage. However, the data in that study were unable to demonstrate the negative impact of high UA levels on muscle strength, as shown here. The different results between these 2 studies may be due to the disparity in age in the sample populations studied. It is logical to hypothesize that the antioxidant role of UA might be more relevant in older subjects than in younger subjects because the skeletal muscles in elderly persons have reduced overall antioxidant capacity to counteract ROS
. Moreover, another explanation is that the mean level (SD) of serum UA is 6.1 (1.2) mg/dL in this study, which is higher than the 5.0 (1.2) mg/dL (in both men and women) from the previous study. It is well known that an increased UA level is related to high inflammatory cytokines
, a contributor to poor muscle strength
In the current study, higher UA levels were associated with poor grip strength and leg extension power by the following possible mechanisms. First, elevated UA concentrations are related positively to systemic inflammation, particularly in the highest category of serum UA
. Indeed, urate crystals contribute to the inflammatory response through the release of pro-inflammatory mediators
, and the risk of urate crystal formation/precipitation increases when the UA concentration exceeds 6.3 mg/dL
. As a prominent marker of systemic chronic inflammation, CRP has been associated with poor muscle strength
[33, 36, 37]. Likewise, Cesari et al.
 and Barbieri et al.
 reported that the pro-inflammatory cytokine interleukin-6 (IL-6), which can promote CRP synthesis
, is an independent predictor of poor muscle strength, especially in subjects with high IL-6 blood levels. In this study, however, the results of an inverted J-shaped curve between serum UA and muscle strength did not appreciably change after additional adjustment for hs-CRP, suggesting that inflammation is not the principal mechanism mediating this association among Japanese adult men. Second, the negative impact of high UA concentrations on muscle strength may be largely due to the serum UA-induced pro-oxidant capacity at higher than normal levels. The antioxidant compound UA may become pro-oxidant when concentrations reach hyperuricemic levels, and the surrounding oxidant milieu, acidity, or the depletion of other local antioxidants may regulate the antioxidant/pro-oxidant switch
. In fact, serum carbonylated protein and skin advanced glycation end products, which are widespread indicators of oxidative damage, have been associated with poor muscle strength in humans
In addition, there is one hypothesis that may explain the lower muscle strength observed in the first UA quartile. A low serum UA level may reflect a decreased antioxidant capability, as UA was considered an important antioxidant in the blood
[6–9]. Moreover, it is worth noting that adjustment for daily energy and protein intakes did not change the results of our study. These data seem to exclude the possibility of a role of malnutrition in the link, although low UA level may be a marker of low nutrient status
, which was associated with poor grip strength
Although this study has revealed important insights into the association between serum UA levels and muscle strength, it does have limitations. First, the association between serum UA and muscle strength is temporarily due to the cross-sectional nature of this study, and thus, a prospective study is necessary to confirm the causality of this association further. Second, we did not perform direct measurement of the UA antioxidant capacity as well as the total antioxidant capacity in the collected samples. Third, because we could not ascertain the site of inflammation in the present study, systemic or chronic inflammation may be present independent of serum UA. Last, the analysis was carried out only in men, and thus, our results cannot be directly generalized to women.