Background Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. Methods We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4 years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). Results The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. Conclusion Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.

中文翻译：

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骨骼肌线粒体功能与认知和运动功能关系的血浆代谢组标记物

背景 较低的骨骼肌线粒体功能与未来的认知障碍和活动能力下降有关，但这些关联的生物学基础尚不清楚。我们检查了骨骼肌线粒体功能、认知和运动功能的代谢组学标志物。方法 我们分析了来自巴尔的摩纵向衰老研究的 560 名参与者（平均年龄：68.4 岁，56% 女性，28% 黑人）的数据，他们通过 31P 获得了骨骼肌氧化能力（运动后磷酸肌酸恢复率，kPCr）的数据。使用 LASSO 模型的磁共振波谱和靶向血浆代谢组学。然后，我们在更大的样本中检查了哪些 kPCr 相关标记也与认知和运动功能相关（n = 918，平均年龄：69.4，55% 女性，27% 黑人）。结果 LASSO 模型显示 24 种代谢物可显着预测 kPCr，其中前 5 种代谢物是不对称二甲基精氨酸、乳酸、溶血磷脂酰胆碱 a C18:1、吲哚乙酸和三酰甘油 (17:1_34:3)，在多变量线性回归中也显着。 kPCr 代谢物评分与认知或运动功能相关，其中 2.5 分钟通常步态速度显示出最强的关联性 (r = 0.182)。五种脂质（溶血磷脂酰胆碱 a C18:1、磷脂酰胆碱 ae C42:3、胆固醇酯 18:1、鞘磷脂 C26:0、十八烯酸）和 2 种氨基酸（亮氨酸、胱氨酸）与认知和运动功能测量相关。结论 我们的研究结果为线粒体功能与衰老引起的认知和身体衰退的发病机制有关这一假设提供了证据，并表明针对特定代谢物可以通过其对线粒体的影响来预防认知和活动能力下降。未来的组学研究有必要证实这些发现，并探索衰老表型中线粒体功能障碍的机制。