ABSTRACT:
Sarcopenia represents a critical geriatric syndrome characterized by the progressive loss of skeletal muscle mass and function. While traditional theories focus on simple atrophy,the upstream molecular mechanisms governing muscle stem cell regenerative failure remain largely underexplored. This study investigates the transcriptomic landscape of aging muscle to identify novel diagnostic biomarkers and therapeutic targets beyond established paradigms. We performed a robust bioinformatic analysis on a large-scale cohort of human muscle biopsies, stratified into Young and Older subjects. To ensure pathophysiological purity, samples subjected to exercise interventions were strictly excluded. Differential Expression Analysis was conducted using Limma (adj. p < 0.05). Functional pathways were mapped via GO, GSEA, PPI, and diagnostic accuracy was evaluated using ROC curve analysis, followed by computational drug repurposing prediction via the DSigDB database. The analysis uncovered a distinct "Regeneration-Blockade" signature in aging muscle. We identified a profound downregulation of DAAM2 (Dishevelled Associated Activator of Morphogenesis 2; LogFC = -1.34; adj. p = 5.81e-47), a critical scaffold protein essential for morphogenesis, alongside a massive upregulation of UNC13C (Unc-13 Homolog C; LogFC = 2.35; adj. p = 2.65e-47), indicating a severe compensatory stress response at the neuromuscular junction. Functional enrichment confirmed the suppression of "muscle tissue development" and "mitochondrion organization" pathways. ROC analysis demonstrated exceptional diagnostic utility, with UNC13C (AUC = 0.991) and DAAM2 (AUC = 0.983) exhibiting near-perfect discrimination between healthy and sarcopenic muscle. Furthermore, drug repurposing analysis identified Fenoterol, a beta-adrenergic agonist known for anabolic properties, as a top candidate compound (adj. p = 4.8e-09) to potentially reverse this pathological signature. We propose a novel pathological hierarchy driven by intrinsic regenerative failure and compensatory neuromuscular struggle. With superior diagnostic accuracy exceeding 98%, these genes represent promising high-precision biomarkers. Additionally, the identification of Fenoterol underscores the potential of repurposing beta-adrenergic modulators to restore regenerative capacity in the elderly.