Zhu Ping, Zhang Jie, Liu Xue-Chun, Song Ming, Lu Bin, Yang Zhi-Cheng, Pan Hui, Jiao Ya-Qiong, Guo Ya-Fei, Chen Fang-Fang, Wang Zhi-Hao, Hu Bo-Ang, Zhong Ming
State Key Laboratory for Innovation and Transformation of Luobing Theory; Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences; Department of Cardiology Qilu Hospital of Shandong University Jinan China.
Department of Cardiology People's Hospital of Lixia District of Jinan Jinan China.
Food Sci Nutr. 2025 Sep 3;13(9):e70841. doi: 10.1002/fsn3.70841. eCollection 2025 Sep.
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.
线粒体功能障碍日益被认为是肌肉减少症发病机制、进展和预后的驱动因素。肌肉量是肌肉减少症的一个基本且客观的组成部分。在一些研究中，相对肌肉量减少被用于定义肌肉减少症。甲基丙二酸（MMA）是线粒体功能障碍和维生素B12缺乏的生物标志物。有证据表明MMA与肌肉功能之间存在负相关，但关于其在低肌肉量和肌肉减少症中的预测和预后价值的人群水平证据仍然稀少。这项队列研究分析了来自美国国家健康和营养检查调查的10414名美国成年人。通过调整后的逻辑回归评估低肌肉量的发生率，同时使用Cox回归和Kaplan-Meier分析评估该人群的全因死亡风险。使用受限立方样条（RCS）模型分析MMA与死亡率的剂量反应关系。亚组分析和敏感性分析检验结果的稳健性。在进行全面协变量调整后，MMA水平升高独立预测该人群低肌肉量的发生率（OR = 1.30，95% CI：1.08 - 1.56，P = 0.007）和全因死亡率（HR = 2.17，95% CI：1.64 - 2.89，P < 0.001）。RCS分析表明，随着MMA浓度升高，死亡率呈单调增加（总体P < 0.001），且无非线性证据（非线性P = 0.057）。Kaplan-Meier生存曲线显示，MMA三分位数之间的死亡率存在显著差异（对数秩P < 0.001），尤其是在老年低肌肉量人群中。亚组分析发现，在终身戒酒者（HR = 3.60，95% CI：2.34 - 5.53，P < 0.001）和糖尿病/糖尿病前期人群（HR = 3.49，95% CI：2.35 - 5.20，P < 0.001）中，低肌肉量与更高的死亡关联。值得注意的是，MMA与充血性心力衰竭存在显著的交互作用（交互作用P = 0.002）。敏感性分析证实了这些关联的稳健性。血清MMA可作为一种双重生物标志物，用于独立预测低肌肉量的发生率和诊断后的死亡率。这些发现强调了其在早期风险检测和预后分层方面的临床实用性，并呼吁开展针对降低MMA的试验，以减轻肌肉减少症的发病机制、进展和预后。
