Skeletal muscle aging is characterized by progressive functional decline and molecular remodeling, yet how different muscle types respond to aging remains incompletely understood. Here, we performed integrated transcriptomic and metabolomic profiling of three functionally distinct muscles-gastrocnemius (GA), soleus (SOL), and tibialis anterior (TA)-from young (3-month) and aged (24-month) C57BL/6J male mice. Our multi-omics approach revealed both shared and muscle-specific molecular signatures of aging. While all three muscles exhibited a core set of 83 commonly altered genes enriched in circadian rhythm, xenobiotic metabolism, and immune signaling pathways, each muscle displayed unique aging trajectories. GA showed 881 differentially expressed genes with prominent alterations in PI3K-Akt and p53 signaling; SOL exhibited 1232 changes emphasizing oxidative phosphorylation and inflammatory responses; TA demonstrated the most extensive remodeling with 1492 altered genes, particularly in extracellular matrix organization and fatty acid metabolism. Metabolomic analysis revealed muscle-specific metabolic reprogramming: GA showed disrupted pentose phosphate and arginine pathways; SOL exhibited altered branched-chain amino acid metabolism; TA displayed TCA cycle perturbations. Notably, the coordination between transcriptomic and metabolomic changes varied by muscle type-GA showed decoupled responses, while SOL and TA demonstrated compensatory inverse relationships. Lipid metabolism emerged as a critical aging-associated process with distinct muscle-specific adaptations: SOL upregulated antioxidant defenses, TA activated compensatory PPAR and PI3K-Akt signaling, while GA showed intermediate responses. Furthermore, receptor-ligand correlation analysis revealed age-dependent reorganization of intermuscular communication networks, with enhanced chemokine signaling and altered growth factor crosstalk. These findings establish that skeletal muscle aging involves both systemic responses and highly muscle-specific molecular adaptations, providing insights for targeted therapeutic strategies against sarcopenia.
