Abstract
<jats:p>Aging of skeletal muscle is traditionally defined by progressive loss of mass and strength; however, the early events that precede these outcomes remain poorly characterized. Here, longitudinal analyses revealed that impaired glucose tolerance arises at 12 months of age in Wistar rats, before detectable changes in body composition, circulating damage markers, or muscle mass. Structural loss was preceded by functional and organizational decline between 15 and 18 months. Animals exhibited marked reductions in strength, mobility, and motor coordination, accompanied by extensive remodeling of muscle architecture, including a shift toward glycolytic fiber composition, extracellular matrix expansion, reduced capillarization, and increased structural heterogeneity. Early supplementation with n-3 polyunsaturated fatty acids, initiated at midlife, significantly improved glucose tolerance, reduced adiposity, and enhanced neuromuscular performance without increasing muscle mass. These functional benefits were paralleled by reduced markers of muscle damage and attenuation of histopathological alterations, indicating preservation of tissue organization rather than hypertrophic effects. Notably, a substantial fraction of these benefits persisted after cessation of supplementation, with animals displaying sustained metabolic and structural advantages at 18 months compared to age-matched controls. Collectively, these findings support a model in which skeletal muscle aging is driven by early loss of functional and structural efficiency rather than mass decline, and demonstrate that transient nutritional intervention can durably reprogram the trajectory of muscle aging. These results highlight a critical window of intervention and position n-3 supplementation as a strategy to induce persistent resilience against age-related functional deterioration.</jats:p>