The Role of Methylmalonic Acid in the Risk of Sarcopenia and All-Cause Mortality Among Individuals With Sarcopenia: Evidence From NHANES.

Mitochondrial dysfunction is increasingly recognized as a driver of sarcopenia pathogenesis, progression, and prognosis. Muscle mass is a fundamental and objective component of sarcopenia. In some studies, relative muscle loss has been used to define sarcopenia. Methylmalonic acid (MMA) is a biomarker of mitochondrial dysfunction and vitamin B12 deficiency. Evidence has shown a negative link between MMA and muscle function, yet population-level evidence on its predictive and prognostic value in low muscle mass and sarcopenia remains scarce. This cohort study analyzes 10,414 U.S. adults from the National Health and Nutrition Examination Survey. Incidence of low muscle mass is evaluated with adjusted logistic regression, while all-cause mortality risk in this population is assessed using Cox regression and Kaplan-Meier analysis. Restricted cubic splines (RCS) model MMA-mortality dose-response. Subgroup and sensitivity analyses test robustness. After full covariate adjustment, elevated MMA level independently predicts low muscle mass incidence (OR = 1.30, 95% CI: 1.08-1.56,  = 0.007) and all-cause mortality (HR = 2.17, 95% CI: 1.64-2.89,  < 0.001) in this population. RCS analysis demonstrates a monotonic mortality increase with rising MMA concentrations ( for overall < 0.001), with no evidence of nonlinearity ( for nonlinear = 0.057). Kaplan-Meier survival curve exhibits significant mortality divergence across MMA tertiles (log-rank  < 0.001), especially in the elder low muscle mass population. Subgroup analysis identifies higher mortality associations in lifetime alcohol abstainers (HR = 3.60, 95% CI: 2.34-5.53,  < 0.001) and diabetic/borderline populations (HR = 3.49, 95% CI: 2.35-5.20,  < 0.001) with low muscle mass. Notably, MMA has significant interaction effects with congestive heart failure ( for interaction = 0.002). Sensitivity analysis corroborates the robustness of these associations. Serum MMA could serve as a dual biomarker for independently predicting low muscle mass incidence and post-diagnosis mortality. These findings underscore the clinical utility for early risk detection and prognosis stratification as well as call for trials targeting MMA reduction to mitigate sarcopenia pathogenesis, progression, and prognosis.