Sarcopenia is defined as a gradual reduction in skeletal muscle mass and function (95). Elevated levels of SU may act as a protective mechanism against free radical damage, potentially preventing muscle protein damage and loss of muscle mass and strength in the elderly population (96). A community-based cross-sectional study using 3079 Chinese adults (963 men and 2116 women) aged 40-75 years revealed that higher SU levels were linked to increased BMD and muscle mass, with the relationship between SU and BMD being influenced by muscle mass (97). Additionally, research on individuals aged 92.8 ± 3.1 years indicated that higher SU levels were associated with improved muscle function, suggesting a potential role of UA in slowing the progression of sarcopenia (98).

A recent cross-sectional study conducted in western China with 4236 adults aged 50 years and older found a negative correlation between SU levels and sarcopenia in both men and women (23). Additionally, the study revealed an inverted J-shaped correlation between SU levels and handgrip strength in women, as well as a positive correlation between SU quartiles and skeletal muscle index regardless of gender. The study recommended that Chinese adults aged 50 years and older with higher SU levels (men: <5.36, 5.36–6.25, 6.25-7.12, ≥7.12 mg/dL; women: <4.26, 4.26–4.94, 4.94-5.72, ≥5.72 mg/dL) may experience increased muscle mass and grip strength, potentially slowing down the progression of sarcopenia (23), which is consistent with previous research findings (97, 98). Furthermore, gender differences in SU levels during adolescence in children and adolescents were noted, likely influenced by sex hormones and pubertal development, with muscle mass playing a role in this variation (99). In this cross-sectional study involving 823 children and adolescents aged 6-18 years of both sexes found that muscle mass contributed to 7.7% and 43.0% of SU variability in girls and boys, respectively (99) ( Table 1 ).

However, abnormally high SU levels (>8 mg/dL) are linked to increased production of ROS and inflammation, both of which contribute to sarcopenia (91). SU at higher concentrations exhibits oxidant properties that are associated with systemic inflammation, leading to a higher risk of muscle strength loss. A cross-sectional study involving 630 Japanese men (aged ≥ 30 years) examined the relationship between SU concentration, grip strength, and leg extension power. The results indicated that HUA (>7.0 mg/dL) was related to poor muscle strength, demonstrating an inverted J-shaped correlation between SU quartiles and muscle strength (100). As age plays a significant role in skeletal muscle composition and function, the adverse effects of UA are more pronounced in younger individuals compared to older individuals. The association between SU levels (men: <5.5, 5.6-6.5, ≥6.6 mg/dL; women: <4.2, 4.3-5.2, ≥5.3 mg/dL) and muscle strength varied across age groups. While a negative correlation was observed in adults aged 20 to 40 years, this relationship reversed in individuals above 60 years old. It is essential to consider both age and muscle strength when setting SU goals for individuals with HUA (101). Both age and SU levels should be considered when evaluating skeletal muscle function and preventing sarcopenia, aligning with the notion that sarcopenia involves age-related muscle mass loss influenced by various factors. For middle-aged and older individuals (≥40 years), higher SU levels (≥5.5 mg/dL) may help safeguard muscle mass and function against sarcopenia. Conversely, younger individuals (aged 20 to 40 years) exhibit a negative correlation between SU levels and muscle strength. In children and adolescents (aged 6 to 18 years), gender and SU levels could directly impact muscle mass. Moreover, excessively high SU levels (>7.0 mg/dL) could contribute to sarcopenia by promoting increased ROS and inflammation ( Table 1 , Figure 2 ).

UA is primarily produced in the liver and to a lesser extent in small intestine (102), adipose tissue (103), and endothelial cells (42), and is predominantly excreted through the urinary tract and sightly through intestine and sweat glands. Several factors can contribute to HUA, including a diet rich in fructose (104), the consumption of exotic organic products (47), and alcohol intake (105, 106). HUA is often associated with metabolic syndrome, which is characterized by abdominal obesity, glucose intolerance, IR, dyslipidemia, and hypertension (47). Elevated SU levels play a role in regulating oxidative stress, inflammation, and enzymes involved in glucose and lipid metabolism, contributing to the deterioration of metabolic homeostasis (47). In fact, HUA and abdominal obesity was shown to synergistically increase the risk of hypertriglyceridemia and low HDL-C in both sexes (107). It is still debatable whether high SU levels are a strong independent predictor of diabetes and precede the development of IR and diabetes (108), because results from some studies indicate IR/hyperinsulinemia might precede HUA (81, 109, 110). Obese individuals with elevated SU levels tend to have lower insulin sensitivity and higher levels of oxidative stress compared to those with normal SU levels (111). A cohort study involving 440 non-diabetic Caucasian subjects with higher SU levels (6.4 ± 0.9) showed a weaker metabolic phenotype and lipid profile, increased 2-hour post-load glucose levels, elevated fasting and 2-hour post-load insulin levels, reduced skeletal muscle insulin sensitivity, and impaired hepatic insulin sensitivity (112) ( Table 2 ).

Skeletal muscle plays a critical role in the effects of insulin and the development of T2D, making sarcopenia a common complication in individuals with diabetes. HUA is frequently seen in conjunction with T2D. A cross-sectional study involving 401 subjects with T2D (209 men and 192 postmenopausal women) was conducted to explore the relationship between SU levels and muscle mass. The study found that higher SU levels were an independent risk factor for men with T2D and sarcopenia (93). Furthermore, a strong positive association was observed between obesity, visceral fat accumulation, and HUA. Another cross-sectional study involving 3393 Chinese participants (43.3% men) investigated the ratio of visceral fat area to leg muscle mass and SU levels. The results indicated a positive correlation between the visceral fat area to leg muscle mass ratio and the risk of HUA in women, even after adjusting for confounding variables. Notably, pre-menopausal women exhibited a higher risk of HUA compared to postmenopausal women as the visceral fat area to leg muscle mass ratio increased. The study also revealed that the highest risk of HUA was observed in individuals with both high visceral fat area and leg muscle mass, placing them in the highest quartile of risk (113) ( Table 2 ).

MCD, also called Type V glycogen storage disease, is an autosomal recessive hereditary condition that results from the lack of glycogen phosphorylase enzyme (the enzyme required for efficient glycogen breakdown) activity in skeletal muscle. Patients with MCD are exercise intolerant because of muscle weakness, fatigue and cramp/pain during moderate- to high-intensity exercise (114). MCD patients often develop HUA because muscular exercise accelerates the degradation of muscle purine nucleotides into inosine and hypoxanthine in the blood that serve as substrates for the synthesis of uric acid in cells of tissues/organ (e.g., liver cells and endothelial cells) expressing xanthine oxidase enzyme, leading to HUA (115). Increased synthesis of UA produces H₂O₂ causing increased oxidative stress. Patients with MCD have elevated level of markers of oxidative stress (8-isoprostanes and protein carbonyls) with insufficient levels of compensatory antioxidant enzyme (mitochondrial superoxide dismutase) activity to fully protect skeletal muscle from oxidative damage. Oxidative stress in McArdle patients can potentially lead to rhabdomyolysis and the subsequent development of fixed myopathy (92) ( Table 2 ).

Patients with HF are intolerant to exercise partly due to skeletal muscle abnormalities caused by ROS. In ischemic tissue, higher activity of XO, that catalyzes UA production from xanthine and hypoxanthine, overproduces ROS (H₂O₂) (36). Skeletal muscle atrophy is a condition of loss of muscle mass caused by various diseases such as diabetes, heart failure, and sarcopenia, resulting in the reduction of total adenine nucleotides, including ATP, ADP, and AMP involved in cellular signaling (36). The elevated level of XO and degradation products such as hypoxanthine, xanthine, in the atrophic skeletal muscle leads to the over production of UA in XO-expressing tissues (36, 116). Higher SU level in patients with heart failure is considered as an independent marker of prognosis and poor exercise tolerance, partly attributed to abnormal skeletal muscle function. In mouse models of HF, myocardial infarction (MI) induced by ligating the left coronary artery, led to skeletal muscle abnormalities, exercise intolerance and eventually to HF (94) and inhibition of XO by febuxostat/allopurinol was shown to prevent XO-derived ROS (H₂O₂) overproduction in XO-expressing tissues and skeletal muscle abnormalities and exercise intolerance (94, 117) suggesting inhibition of XO-derived ROS production can prevent skeletal muscle abnormalities.

In hemodialysis patients, SU level was suggested as a good marker positively correlated with body composition parameters, muscle function, inflammation, and quality of life body composition (118). In a single-center retrospective cohort study on 802 peritoneal dialysis patients (with 464 men and an average age of 46.2 ± 14.2 years), the SU levels in middle-aged and elderly male patients were shown positively associated with appendicular skeletal muscle mass, suggesting a significant impact of appendicular skeletal muscle mass on the relationship between SU and peritoneal dialysis-related mortality (119) ( Table 2 ). Additionally, in a cross-sectional study on 113 Brazilian kidney transplant patients (75 men and 38 women), SU level was shown positively correlated with muscle mass (fat-free mass, appendicular muscle mass, muscle mass index, and appendicular muscle mass index) and strength, but not to functional capacity (120) ( Table 2 ). A study conducted on a Tasmanian cohort of older adults, consisting of 409 individuals aged 50-79 years (205 men) over the 10-year period, showed association of elevated level of asymmetric dimethylarginine (ADMA) in the blood with the decrease in hand grip and knee extension strength (121). Furthermore, increase in SU level was shown associated with the decline in leg muscle strength over the same 10-year period (121). In a genome-wide association study (GWAS), a single nucleotide polymorphism (SNP) rs1125718 near the WISP1 gene was shown associated with ADMA levels (121). These findings suggest that higher levels of ADMA and SU at baseline may contribute to age-related muscle strength decline, highlighting potential new targets for preventing muscle strength loss over time (121) ( Table 2 ).

Renal hypouricemia (RHUC) was shown as an important risk factor for EIAKI and urinary stones (32). There are two types of RHUC described, RHUC1 and RHUC2. RHUC1 is caused by mutations in the SLC22A12 gene (encoding the urate reabsorption transporter URAT1), while RHUC2 is caused by mutations in the SLC2A9 gene (encoding the urate reabsorption transporter GLUT9 isoforms, GLUT9a and GLUT9b). A single−center study from China reported that a proportion of 10 out of 19 patients suffered from EIAKI, the prognosis of which was favorable (122). A large-scale cross-sectional study from Japan found that genetic hypouricemia in men is more strongly involved in EIAKI than transient hypouricemia which is mostly influenced by female hormones (123). Another large-scale cross-sectional study of Japanese schoolchildren discovered that hypouricemia in children including RHUC, as a main cause of EIAKI, was a crucial clinical problem, over and above HUC. The school-age children were investigated, who were younger than the overwhelming majority of people with EIAKI, for reducing the risk of subsequent EIAKI via offering more care and guidance (124). It was suggested that after exhaustive exercise, RHUC patients develop higher concentration of urate in the lumen of proximal straight tubule and/or thick ascending limb of Henle’s loop that could stimulate the luminal TLR4-MyD88-PI3K-mTOR to activate the NLRP3 inflammasome and release IL-1β, which might cause the symptoms of EIAKI (32).

Osteoarthritis (OA), one of the top two leading causes of disability worldwide affecting about 7% of the global population, is a chronic, heterogeneous and degenerative joint disease characterized by degeneration of articular cartilage, sclerosis of subchondral bone (just below the cartilage), and osteophyte (growth of bone at the edges of joints/spine) formation, which is considered a leading cause of activity limitation and disability among the elderly population. OA has multiple clinical phenotypes such as abnormal joint tissue metabolism followed by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function (125). The diverse overlapping components of molecular endotypes of OA include bone and cartilage, inflammatory, metabolic and low repair (126). The etiology of OA is multifaceted, involving a complex interplay of metabolic, genetic, mechanical, and inflammatory factors (127). The inflammation of OA could be independent of NLRP3 activation because stress-induced cartilage degradation, in OA cartilage explants from OA patients, was reported not linked to increased IL-1β production (128). NLRP3-deficient mice also showed similar cartilage degradation upon stimulation by inflammatory agents like LPS, IL-1α, and tumor necrosis factor (TNF)α-induced activity of MMP-3, MMP-9, and MMP-13 in cultured chondrocytes and in NLRP3(-/-) chondrocytes (128). Positive associations between SU levels and OA were reported by several studies (129–131) especially in patients of hip or knee OA with elevated SU levels (132, 133). Additionally, it was reported that SU levels may serve as a biomarker for OA progression (134) as SU levels can differ between patients with non-progressive and progressive OA over time, as demonstrated by changes in X-ray joint space narrowing (134). Recently, in a prospective cohort study with a total of 4671 American participants (age range: 20 to 85 years old), including 2988 females and 1683 males, a nonlinear J-shaped relationship between SU levels (with the cut-off values of 5.6 mg/dl for females and 6.2 mg/dl for males) and all-cause mortality in females and males with OA has been reported (135). However, recent data from the Seventh Korea National Health and Nutrition Examination Survey in 2016 suggested no significant association of SU levels with OA in the Korean population, as some patients with OA actually had lower SU levels compared to those without OA (136) ( Table 3 ).

OA affects about 30 million individuals and gout affects about 8.3 million individuals though about 43 million individuals in the U.S. are diagnosed with HUA (27). OA is a low-grade inflammatory condition primarily caused by wear and tear on joints that causes cartilage erosion symmetrically on both sides of the body leading to morning stiffness for short period of time with little or no swelling. Gout, a common metabolic disorder, is the MSU crystal-induced the most common inflammatory arthritis with episodic flares of intense inflammation related to long standing HUA (137). Tophaceous gout occurs when MSU crystals form white deposits called tophi around joints and soft tissues causing restricted joint function. Deposition of MSU crystals were detected in various bodily structures such as joints, cartilage, synovial bursa, tendons, or soft tissues (138). Gout and OA frequently coexist clinically in the same patient (139). However, the pathophysiologic relationship between the two remains elusive. A nested case-control study revealed that joints with a history of gout attacks were more likely to be affected by OA (140). Specifically, the distal interphalangeal joint of the finger, knee, mid-foot, and the first metatarsophalangeal joint showed a 12.7-fold, 3.1-fold, 2.9-fold, and 2.1-fold increased risk of clinically defined OA when attacked by gout, accompanied by chronic pain symptoms (141). A cross-sectional study, which included three cohorts of subjects aged 50 years or older with joint pain, found that individuals with gout had an increased risk of hand and foot OA but a decreased risk of knee OA (142). Another small cohort study focusing on middle-aged to elderly men with HUA, gout, or neither, revealed an elevated risk of knee OA in patients with gout, with no significant differences observed between patients with HUA and the other groups (143). Additionally, a cohort study involving 51,858 subjects and 1,435 cases of incident knee arthroplasty showed a significantly higher prevalence of knee arthroplasty among women with gout (24). Furthermore, a case-control study with 39,111 cases and 39,111 controls indicated that gout was associated with a 1-, 2-, 5-, and 10-year risk of OA (144).

Gout also promotes cartilage degradation due to the direct effects of MSU crystals. Studies have shown that joints (especially metatarsophalangeal joint, mid-foot, knee and finger distal interphalangeal joints) affected by acute attacks of gout also display clinical or radiographic features of OA (86, 87) suggesting that OA may predispose to the localized deposition of MSU crystals. It remains elusive whether gout promotes the development or progression of OA but aging and obesity remain as significant risk factors for both OA and gout. In a cross-sectional study, higher fat mass, increased muscle mass, and the presence of osteophytes were shown associated with the higher risk of tophaceous gout (145). Evidence from epidemiological studies supports an association between gout and OA (127). Compared to the painful flares of gout, the pain in OA is less intense and more variable. OA but not gout commonly affects hip, and wrist however OA and gout share some joints, like the distal interphalangeal joints, the first metatarsal phalangeal joints and knees (27). Poor renal excretion of urate is an important risk factor for gout but not for OA. OA genetics relates most commonly to cartilage biology and body mass index (BMI), whereas gout genetics relates largely to renal handling of urate. Men are more likely to develop gout, whereas women are more likely to develop OA indicating gender difference might play an important role in both gout and OA. UA has been hypothesized as a pathological link between gout and OA but current therapies for OA include only analgesia and joint replacement. The role of MSU crystal-induced inflammation in both OA and gout could be a possible shared pathway for pathogenesis. MSU and calcium pyrophosphate dihydrate (CPPD) crystal deposits in the talus were reported with cartilage degradation (146) suggesting these lesions are biomechanically induced. Soluble form of UA/urate in synovial fluid of knee OA was suggested to be strongly and positively associated with OA severity with pro-inflammatory cytokines like IL-1β and IL-18 (produced by uric acid-activated inflammasomes) in the synovial fluid (147). Thus, it was hypothesized that urate from systemic circulation or released from dying chondrocytes, might get into the joint and form micro-particles with proteoglycan released from dying cells. These micro-particles may then trigger the innate immunity and NALP3 inflammasome pathway (147). MSU crystals may trigger toll-like receptor 4 (TLR-4) primed by the reservoir of lipopolysaccharide (LPS) from gastrointestinal microbiome of obese people leading to phagocytosis, inflammasome activation, and subsequent inflammation and joint damage (148). Peripheral blood mononuclear cells (PBMCs), pre-treated with soluble UA and stimulated by MSU crystals, were shown to enhance IL-1β, IL-6 production (90) suggesting the condition of HUA may influence inflammatory responses by facilitating IL-1β production in peripheral blood leukocytes. IL-1β via activation of the MAPK (mitogen-activated protein kinase) can elevate the levels of matrix metalloproteinases that can cause cartilage matrix protein degradation (149). MSU is also linked to complement activation, direct T cell activation, and mast cell degranulation, all of which may be involved in the pathogenesis of OA (150, 151). The overlap between OA and gout/HUA suggests the efficacy of urate-lowering therapies for OA could be an interesting hypothetical strategy.

Previous research has established a reciprocal relationship between UA and OA (27). In a Korean longitudinal cohort study aimed at validating the potential link between gout and OA, it was found that over a 3-year period, SU levels in subjects without gout were inversely related to patellofemoral cartilage loss. However, SU was not identified as a risk factor for OA progression in the study, which was consistent with previous findings (136). Nonetheless, large-scale longitudinal studies involving diverse populations are needed to further elucidate this association (152). Lastly, an American cross-sectional study involving 2,213 individuals, including 412 with asymptomatic HUA, revealed that asymptomatic HUA was associated with an increased risk of OA, particularly in adults over the age of 60 without obesity (25) ( Table 3 ). Clinical epidemiological studies on gout involving tendons are rare. Rotator cuff tears are a common cause of shoulder disability, and surgery is often chosen to restore function. In a 7-year Chinese longitudinal cohort study, 32,723 patients with gout and 65,446 control individuals participated at a 1:2 ratio. Patients with gout, especially those under 50 years old and not on hypouricemic medication, had a higher risk of needing rotator cuff repair surgery. Strict control of UA levels with hypouricemic medication could reduce this risk (153). Generally, SU levels should be kept below 6.0 mg/dL. For patients with tophi, initial SU levels should be below 5.0 mg/dL to dissolve tophi (138) ( Table 3 ).

Spinal gout, a rare disease, can often be mistaken for infections or neoplastic lesions, posing a challenge in diagnosis. In a case study, a patient with a long history of HUA and gout with progressive impairment of walking, MRI features revealed vascularized gouty tophi in the cervical spine in areas of low signal intensity both on T1 and T2 images and pathologic examination of the specimen demonstrated presence of fibrous tissue and amorphous MSU deposits and bone erosions by the MSU crystal deposits (154). In another case study, a 71-year-old man with a long history of HUA and gout (multiple tophi in elbows, hands, knees, and toes) with progressive quadriparesis (muscle weakness in both legs and both arms), severe cervical spondylosis and a herniated cervical disc at the C3-C4 level on MRI, was found to have intradiscal chalky white granular material called gouty tophus (155). Though spinal involvement in gout and cervical spinal cord compression caused by gout are uncommon, it should be considered in all patients presenting myelopathy and history of gout and HUA (156).

Intervertebral disc degeneration (IDD) is a common musculoskeletal disorder. Several case reports have described the presence of tophi in the endplate (a bilayer of cartilage and porous bone) or intervertebral disc (IVD) of patients with HUA or gout, and severe IDD. UA with its potent antioxidant activity helps maintain the stability of the IVD, but higher levels of UA production associated with generation of higher level of ROS (H₂O₂) production can lead to accelerate IDD (5). Moreover, MSU crystals accumulated in the endplate and IVD, can cause mechanical damage and inflammatory reactions that worsen IDD. In a recent study involving 1375 Chinese patients, it was found that there was a U-shaped relationship between SU levels and IDD, especially among men (26). The study also revealed a positive correlation between SU and lumbar spine BMD in American men within a certain range (SU < 5 mg/dL), although this correlation was no longer significant when SU levels exceeded 5 mg/dL. Factors such as race and age were found to influence this relationship (157). However, in a recent Mendelian randomization study, no causal relationship between SU and IDD was reported (158) ( Table 3 ).