Investigating the Role of Tyrosine Metabolism and Critical Genes in the Pathogenesis of Sarcopenia
10.13865/j.cnki.cjbmb.2025.06.1194
- VernacularTitle:探讨酪氨酸代谢及关键基因在肌肉减少症发病机制中的作用
- Author:
Yang ZHANG
1
;
Qiang-Man WEI
1
Author Information
1. 国家体育总局体育科学研究所,北京 100061
- Publication Type:Journal Article
- Keywords:
sarcopenia;
tyrosine metabolism(TYR metabolism);
machine learning;
regression model-ing;
mendelian randomization(MR)
- From:
Chinese Journal of Biochemistry and Molecular Biology
2025;41(7):1048-1061
- CountryChina
- Language:Chinese
-
Abstract:
Sarcopenia is closely linked to metabolic dysregulation in the elderly and shows a major patho-logical phenotype of functional decline.Although tyrosine metabolism has been shown to be aberrantly ac-tivated in various aging-related disorders,its regulatory role and quantitative causal relationship with clin-ical muscle function in sarcopenia remain underexplored.We integrated three independent bulk transcrip-tomic datasets(total n=487)and applied linear models for microarray data(Limma)differential ex-pression,gene set enrichment analysis(GSEA)pathway analysis,and weighted gene co-expression net-work analysis(WGCNA)and identified 33 tyrosine metabolism-related genes.Cross-validation using least absolute shrinkage and selection operator(LASSO)regression,random forest(RF),and support vector machine-recursive feature elimination(SVM-RFE)algorithms highlighted four key regulators:FOXO1,ADH1B,DUSP4,and IDO1.Single-cell RNA sequencing(scRNA-seq)data(n=24 573 cells)combined with single-cell metabolism scoring(scMetabolism)were used to build cell-level linear regression models linking gene expression to tyrosine metabolic activity(e.g.,FOXO1:y=1.7542x+0.9345,R2=0.79).Two-sample Mendelian randomization(MR)analysis was conducted to infer caus-al effects on muscle strength phenotypes.The results showed that FOXO1 was highly expressed in satellite cells(3.1-fold vs.other cell types,P=1.4 × 10-8)and showed a strong positive correlation with meta-bolic activity.MR analysis indicated that higher FOXO1 expression significantly increased the risk of grip strength decline(β=-0.23,P=2.1 × 10-6),whereas IDO1 exhibited a protective causal associa-tion(β=0.17,P=4.3× 10-4).A multivariable risk model based on these four genes achieved an area under the curve(AUC)of 0.86 in an independent validation cohort,outperforming traditional clini-cal indicators(ΔAUC=0.12,P=0.003).In sum,by integrating multi-algorithm feature selection,single-cell quantitative modeling,and genetic causal inference,this study systematically elucidates the central role of tyrosine metabolism in sarcopenia and provides a quantitative framework for molecular sub-typing and targeted interventions.
