Introduction

Uric acid (UA), an end product of purine metabolism with antioxidant properties, has been associated with muscle-related outcomes, including muscle mass and muscle strength, particularly among middle-aged and older adults [1–3]. Notably, stronger associations between UA and muscle-related outcomes have been observed in individuals with lower body mass index (BMI) [4]. However, findings have been inconsistent, and a recent Mendelian randomization study did not support a causal relationship between serum UA levels and muscle-related traits [5]. These findings suggest that UA may reflect underlying metabolic or oxidative processes rather than act as a direct causal factor. Therefore, the role of UA in skeletal muscle health remains incompletely understood.

Among the various components of muscle health, muscle strength is increasingly recognized as a more clinically relevant indicator than muscle mass alone. Age-related decline in muscle health has been widely investigated within the framework of sarcopenia, and international consensus groups [6,7], including the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) and the Asian Working Group for Sarcopenia (AWGS), have proposed diagnostic criteria that place greater emphasis on muscle strength than muscle mass [8,9]. Furthermore, the recently updated AWGS 2025 consensus has shifted its focus from sarcopenia to broader muscle health [10].

Although sarcopenia has traditionally been considered an age-related condition, it has also been reported in younger populations [11]. Early muscle impairment in young adults has been associated with lifestyle- and health-related factors such as insufficient energy and protein intake, physical inactivity, chronic illness, and hormonal imbalance [12]. Large-scale epidemiological studies have reported that approximately 10% of individuals in their 20s–30s exhibit sarcopenia-related characteristics, with a higher prevalence observed in Asian populations [13,14]. In Japan, the KEIJI-U study of first-year university students reported a low prevalence of AWGS-defined sarcopenia (approximately 1%); however, underweight individuals were relatively common (16–17%) and exhibited significantly lower skeletal muscle mass and handgrip strength than their normal-weight counterparts [15]. Nevertheless, the sarcopenia-related diagnostic criteria currently applied to young adults were originally developed for older populations, and their applicability to younger individuals remains uncertain [8,9].

Among young adults, underweight women may represent a particularly vulnerable population with respect to muscle health because of chronically low energy availability, reduced fat and muscle reserves, and potential hormonal disturbances associated with menstrual abnormalities [11]. Despite the relatively high prevalence of underweight status among young women in Japan, little is known about the relationship between serum UA and muscle-related parameters in this population. Therefore, this study investigated the associations between serum UA and muscle-related parameters, including handgrip strength and skeletal muscle mass, in underweight female university students.

Methods

This cross-sectional study was conducted at Shimane University, Japan, between 2022 and 2024. Underweight female university students (BMI < 18.5 kg/m²) were identified through routine health checkups and referred to the university Health Service Center for further assessment. Eligible students were invited to participate in the study. A total of 93 underweight female students were enrolled. Of these, 20 were excluded because blood test data were unavailable, leaving 73 participants for the final analysis.

Results

Baseline characteristics

There were no significant differences in age, BMI, or handgrip strength between the included (n = 73) and excluded participants (n = 20).

Among the 73 participants, the mean age was 19.2 ± 1.4 years, and the mean BMI was 17.2 ± 0.9 kg/m². Mean SMI and handgrip strength were 5.1 ± 0.5 kg/m² and 21.9 ± 3.9 kg, respectively. Mean daily energy intake was 1,547 ± 315 kcal/day, and the median physical activity level was 693 (396–1,188) MET-min/week, with 38.4% of participants classified as low physical activity (<600 MET-min/week). No participants screened positive for AN. Laboratory measurements showed a mean serum UA level of 3.9 ± 0.7 mg/dL, and 11.0% of participants had a UA level ≤3.0 mg/dL. Mean serum creatinine and eGFR were 0.5 ± 0.1 mg/dL and 122 ± 21 mL/min/1.73 m², respectively (Table 1).

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Table 1. Baseline characteristics of the participants.

https://doi.org/10.1371/journal.pone.0355968.t001

Using the AWGS 2019 criteria (SMI < 5.7 kg/m²), 63 of 73 participants (86.3%) were classified as having low muscle mass. In a sensitivity analysis using an alternative cutoff of SMI < 5.0 kg/m² proposed in a validation study of young Japanese women [20], 24 participants (32.9%) were classified as having low muscle mass, resulting in reclassification of 39 participants (53.4%).

Serum UA levels according to muscle mass and strength status

Serum UA levels differed significantly among the three muscle status groups (one-way ANOVA, p = 0.026; Table 2). Serum UA levels were lowest in participants with both low muscle mass and reduced handgrip strength. Post hoc analysis showed that this group had significantly lower serum UA levels than the low muscle mass only group (3.4 ± 0.7 vs. 4.1 ± 0.6 mg/dL, p = 0.020). No significant differences were observed in the other pairwise comparisons.

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Table 2. Serum UA levels according to muscle mass and handgrip strength status.

https://doi.org/10.1371/journal.pone.0355968.t002

Associations between serum UA and muscle-related parameters

Serum UA was positively correlated with handgrip strength (r = 0.273, p = 0.013). No significant correlation was observed between serum UA and SMI (r = 0.080, p = 0.503) (Fig 1).

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Fig 1. Relationship between serum uric acid and muscle-related parameters.

Scatter plots show the associations between serum UA and (A) handgrip strength and (B) SMI in underweight young women. The solid line represents the fitted linear regression line, and the outer lines indicate the 95% confidence bands.

https://doi.org/10.1371/journal.pone.0355968.g001

Multivariable linear regression analysis

In the age-adjusted model (Model 1), serum UA was positively associated with handgrip strength (B = 1.605, 95% CI 0.316–2.893, p = 0.015). After further adjustment for SMI and eGFR (Model 2), the association remained significant (B = 1.186, 95% CI 0.061–2.311, p = 0.039). This association persisted after additional adjustment for daily energy intake and physical activity (Model 3; B = 1.245, 95% CI 0.060–2.431, p = 0.040). SMI was independently associated with handgrip strength (B = 4.605, 95% CI 2.723–6.487, p < 0.001), whereas age, eGFR, daily energy intake, and physical activity were not significantly associated with handgrip strength (Table 3). All VIFs in Model 3 were below 1.3, indicating no evidence of problematic multicollinearity.

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Table 3. Multivariable linear regression analysis of factors associated with handgrip strength.

https://doi.org/10.1371/journal.pone.0355968.t003

Discussion

In this exploratory study of underweight young women, serum UA levels were associated with handgrip strength but not with skeletal muscle mass. In multivariable linear regression analyses, serum UA remained independently associated with handgrip strength after adjustment for age, SMI, eGFR, daily energy intake, and physical activity. These findings suggest that serum UA may be more closely associated with muscle function than with muscle mass in underweight young women.

Sarcopenia, characterized by declines in muscle strength and muscle mass, is a widely used construct for evaluating muscle health in clinical research [6,10]. Previous studies examining the association between UA and sarcopenia have reported positive, negative, and nonlinear relationships. In a four-year cohort study of 5,086 Chinese adults aged ≥45 years, men in the highest UA quartile (≥5.7 mg/dL) had a significantly lower risk of incident sarcopenia than those in the lowest quartile (HR 0.57, 95% CI 0.41–0.80), whereas no significant association was observed in women [1]. Higher UA levels within the normal range have also been associated with greater muscle mass and handgrip strength in observational studies [2,3]. In contrast, NHANES data suggested a U-shaped relationship between UA and muscle health. Participants with UA ≥ 6.3 mg/dL had a higher prevalence of low appendicular lean mass relative to BMI than those in the lowest UA group (10.5% vs. 5.3%), with the lowest risk observed at approximately UA 4.5–5.5 mg/dL [4]. Furthermore, a recent bi-directional Mendelian randomization study found no causal effect of serum urate on handgrip strength, lean mass, or gait speed [5]. Taken together, these findings suggest that serum UA may be associated with muscle health, although it may primarily reflect underlying metabolic or oxidative processes rather than directly influence skeletal muscle.

The inconsistent findings across studies may be partly explained by differences in age, sex, and nutritional status among study populations. Previous studies have suggested that moderately higher UA levels are associated with better muscle health in middle-aged and older adults, whereas the relationship appears less consistent in younger populations [1,2,4]. In addition, estrogen enhances renal UA excretion, resulting in lower UA levels in premenopausal women, which may partly contribute to sex-related differences in the association between UA and muscle-related outcomes.

UA is the end product of purine metabolism and is closely linked to cellular energy turnover. Under physiological conditions, efficient adenosine triphosphate (ATP) resynthesis limits purine degradation and maintains UA production within a normal range. Conversely, energy deficiency may alter ATP metabolism and purine turnover, thereby influencing serum UA levels [21]. Miller et al. demonstrated that fasting and glucocorticoid/FoxO3 signaling promote purine degradation and release from skeletal muscle, resulting in increased UA production through xanthine oxidoreductase-dependent pathways [22]. However, prolonged undernutrition may ultimately reduce the availability of substrates required for purine metabolism. In the present study, participants had a mean energy intake of approximately 1,550 kcal/day, which was below the estimated energy requirement even for Japanese women aged 18–29 years with a low physical activity level (1,700 kcal/day) [23]. Furthermore, 38.4% of participants had low physical activity and 45.1% reported dysmenorrhea, indicating that this cohort exhibited several characteristics commonly observed in underweight young women. These findings suggest that many participants may have had suboptimal nutritional and physiological status. Lower serum UA levels may therefore reflect altered nutritional and metabolic conditions in this population.

In addition, serum UA may be associated with muscle function through its antioxidant properties. UA is one of the major endogenous antioxidants in humans [21]. Lower serum UA levels may reduce antioxidant capacity and increase oxidative stress. Oxidative stress has been reported to impair muscle protein homeostasis and contractile function, potentially contributing to reduced muscle strength [24]. These mechanisms may partly explain why serum UA was more closely associated with muscle strength than muscle mass in the present study. However, these proposed mechanisms should be interpreted with caution because this was a cross-sectional study and oxidative stress and metabolic biomarkers were not assessed.

Another important consideration is the applicability of the diagnostic criteria used in this study. The AWGS 2019 criteria were originally developed for older Asian adults and may not be fully applicable to younger populations. A sensitivity analysis using an alternative SMI cutoff of <5.0 kg/m² for young Japanese women [20] reduced the prevalence of low muscle mass from 86.3% to 32.9% in our cohort. This marked difference highlights the need for age-specific diagnostic criteria for young women. Nevertheless, we defined low muscle mass and low muscle strength according to the AWGS 2019 criteria because they represent the current consensus diagnostic criteria for Asian populations and facilitate comparison with previous studies. For handgrip strength, published age-specific normative data for healthy women aged 20–39 years reported 5th percentile handgrip strength values of 18–20 kg [7], which closely correspond to the AWGS cutoff (<18 kg). Therefore, the classification of low muscle strength is unlikely to differ substantially. Our primary regression analyses evaluated SMI and handgrip strength as continuous variables; therefore, the overall conclusions regarding the association between serum UA and muscle function were unlikely to be materially influenced by the choice of categorical cutoff.

This study has several limitations. First, its cross-sectional design precludes causal inference, and the relatively small sample size, particularly the small subgroup of participants with both low muscle mass and low muscle strength, may have limited statistical power. However, this study focused on a highly specific population of underweight young women who underwent comprehensive assessments, which limited the number of eligible participants while reducing potential confounding factors. Although body fat percentage may be a useful indicator of nutritional status, it was not included in the final multivariable model because it is related to skeletal muscle mass. Given the relatively large number of covariates compared with the sample size, further inclusion of variables might have increased the risk of over-adjustment and overfitting. In addition, because participants were recruited from a single university, the findings may not be generalizable to other populations, including young men or young adults with normal body weight. Second, muscle mass was assessed using a single BIA device rather than dual-energy X-ray absorptiometry (DXA). Because BIA is influenced by hydration status and is less accurate than DXA, measurement error cannot be excluded. Third, renal function was assessed using creatinine-based eGFR rather than cystatin C-based eGFR. Because creatinine-based eGFR is influenced by muscle mass, residual confounding related to renal function cannot be excluded [25,26]. Fourth, detailed nutritional factors and female sex hormone levels, both of which may influence muscle health and UA metabolism, were not assessed. In addition, serum UA levels may vary across the menstrual cycle because of hormonal fluctuations [27], and underweight women may experience menstrual irregularities associated with altered hormone levels. Finally, oxidative stress and metabolic biomarkers were not assessed; therefore, the biological mechanisms underlying the observed association remain speculative. Future longitudinal studies incorporating comprehensive nutritional, hormonal, and metabolic assessments are warranted.

Despite these limitations, little is known about the association between serum UA and muscle-related parameters in underweight young women. Therefore, the present findings provide preliminary evidence in this understudied population.

In conclusion, serum UA was associated with handgrip strength but not with skeletal muscle mass in underweight young women. These findings suggest that serum UA may be more closely related to muscle function than to muscle mass in this population. Further prospective studies are warranted to clarify the underlying mechanisms and clinical implications of this association.