Journal of Biomedical Advancement Scientific Research

Abstract

Background: Sarcopenia is closely associated with metabolic deterioration during aging, yet the molecular mechanisms distinguishing pathological muscle decline from healthy aging remain incompletely understood. This study aimed to identify molecular signatures linking sarcopenia, metabolic dysfunction, and healthy aging through integrative analysis of skeletal muscle transcriptomic data.

Methods: Four independent transcriptomic datasets comprising 201 participants were analyzed across sarcopenia, metabolic dysfunction, healthy-aging, and validation cohorts. Differential expression analysis was followed by cross-phenotype integration, functional enrichment, protein–protein interaction network analysis, and independent validation. Receiver operating characteristic analysis and correlations with available muscle and metabolic parameters were additionally performed for prioritized candidate genes.

Results: A total of 426 differentially expressed genes were identified in sarcopenia and 518 in metabolic dysfunction. Cross-phenotype integration identified 37 shared genes, including 29 with concordant expression patterns. Twelve genes exhibited preserved or opposite expression patterns during healthy aging. Functional enrichment demonstrated predominant involvement of oxidative phosphorylation, mitochondrial organization, fatty-acid metabolism, AMPK signaling, and cellular stress responses. Network analysis prioritized PPARGC1A, SIRT3, TFAM, CPT1B, and FOXO3 as principal candidate genes. All five showed consistent differential expression in the independent validation cohort. A composite five-gene signature achieved an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.81–0.98) for distinguishing sarcopenia from non-sarcopenic controls.

Conclusion: Sarcopenia and metabolic dysfunction share a molecular signature characterized by impaired mitochondrial and metabolic regulation, whereas preservation of these pathways may contribute to healthy skeletal muscle aging. The identified genes provide candidate molecular markers and targets for further investigation of metabolic resilience and sarcopenia prevention.